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Introduction: Sexual dysfunction is more prevalent in postmenopausal women., Aims: To prospectively evaluate and compare the effects of hormone therapy (HT) regimens, oral and vaginal estradiol, estradiol + drospirenone and tibolone, on sexual function in healthy postmenopausal women., Methods: The study included 169 consecutive healthy postmenopausal women, and the women were divided into two groups: 111 women received HT, and 58 women received no treatment and served as a control group. As an HT, 23 women with surgically induced menopause received oral 17-beta estradiol. The rest of the women with natural menopause were prospectively randomized: 22 received oral 17-beta estradiol + drospirenone daily, 42 received oral tibolone, and 24 received vaginal 17-beta estradiol. Sexual function was evaluated with a detailed 19-item questionnaire, the female sexual function index, including sexual desire, arousal, lubrication, orgasm, satisfaction, and pain., Main Outcome Measures: The differences in sexual function were compared before and 6 months after the treatment in all women., Results: Total sexual function score increased from 19.81 +/- 7.15 to 22.9 +/- 6.44 in the HT group and decreased from 21.6 +/- 8.69 to 17.6 +/- 5.7 in the control group, revealing a significant difference from baseline to post-treatment between the two groups (P = 0.000). The highest improvement in total score and arousal was achieved with the oral 17-beta estradiol (P = 0.000 and P = 0.000, respectively). The highest improvement in lubrication was achieved with the oral and vaginal 17-beta estradiol groups (P = 0.000). The highest improvement in orgasm was achieved with the tibolone group (P = 0.000). The highest improvement in pain was achieved with the oral and vaginal 17-beta estradiol groups (P = 0.000)., Conclusions: HT provided significant improvement in sexual function compared to women receiving no treatment, and therefore, HT regimens should be suggested for improvement in sexual functioning of postmenopausal women.

Objective: To compare cognitive function in postmenopausal women receiving continuous hormone replacement therapy and those receiving tibolone., Study Design: This was a 6-month, prospective, single-blind, single center, randomized study. A total of 50 healthy, postmenopausal women were enrolled. In the end, 40 women completed the 6-month follow-up. One group (23 subjects) received conjugated equine estrogens (CEE), 0.625 mg/d, and medroxyprogesterone acetate (MPA), 5 mg/d. The other group (17 subjects) received tibolone, 2.5 mg/d. Their serum estradiol levels and Cognitive Abilities Screening Instrument (CASI) and Mini-Mental State Examination (MMSE) scores were obtained before starting and after 3 and 6 months of treatment., Results: There was a significant increase in the serum estradiol level in the CEE + MPA group, especially after 3 months of treatment, but there was no increase in the estradiol level in the tibolone group. The CASI and MMSE scores of the CEE + MPA group and the tibolone group after 3 and 6 months of treatment showed no significant difference between the two groups apart from the MMSE at the 3-month follow-up. We saw an increasing trend in CASI and MMSE scores after treatment in both groups; however, the increases were not statistically significant. The rate of increase of both CASI and MMSE scores in the CEE + MPA group was greater than in the tibolone group, though the difference was not significant., Conclusion: This preliminary study demonstrated that both CEE + MPA and tibolone can preserve cognitive function and may be able to prevent cognitive decline in postmenopausal women during short-term treatment. Our results also show that continuous, combined CEE + MPA seems to be marginally more effective than tibolone in improving cognitive processes; however, long-term study is needed to follow-up such effect.

Objectives: Evaluation of the impact of an oral contraceptive on body weight with a comparison ofwomen who completed versus women who prematurely discontinued intake., Methods: Data on body weight were retrospectively analyzed from four large prospective clinical trials with an oral contraceptive containing 20 microg ethinylestradiol and 75 microg gestodene (EE/GSD). A total of 1971 young fertile women were included in the evaluation, and 1467 completed 12 cycles., Results: We found no clinically relevant change of body weight during treatment with an oral contraceptive containing 20 microg ethinylestradiol and 75 microg gestodene in the vast majority of users after 12 treatment cycles. The mean change of body weight was less than 0.3 kg in this time period for all users. Nearly 70% of women experienced a minor change in their body weight of +/- 2 kg. An additional 13% lost more than 2 kg body weight in the course of 12 treatment cycles. A total of 11% increased their weight by 2-4 kg. A total of 1255 (85.5%) of women had a body mass index (BMI) of < or = 25 at baseline compared to 1253 (85.4%) after 12 cycles of treatment. There was no significant difference in the change ofbody weight between the women completing 12 cycles of treatment and those who prematurely discontinued EE/GSD., Conclusions: This retrospective analysis confirms that there was only a negligible change of body weight during intake of an oral contraceptive containing 20 microg ethinylestradiol and 75 microg gestodene. There was no difference in weight change between the women completing the study or discontinuing intake.

We compared the effects of two third-generation progestogens, desogestrel (DSG) and gestodene (GSD), on coagulation and fibrinolysis in Brazilian users of oral contraceptives (OCs). Forty-six women were evaluated before treatment and after six cycles of treatment. The coagulation, anticoagulant, and fibrinolytic systems were investigated. During the use of the DSG-containing OC, the activity of factors VII, VIII, IX, X, and XII increased significantly whereas the GSD-containing OC caused no changes in coagulation parameters. Concerning the anticoagulant pathways, the DSG-containing OC increased protein C levels and decreased total protein S levels, and the GSD-containing OC only decreased total protein S. Both OCs increased plasminogen activity, although the DSG-containing OC increased fibrin degradation products levels and decreased the tissue plasminogen activator antigen. In conclusion, we have found that in Brazilian women the effects of DSG and GSD on hemostatic parameters are different and, therefore, third-generation progestogens may not contribute equally to the thrombotic risk.

Postmenopausal women taking oestradiol 17-beta 2 mg daily were randomized to receive either 25 or 50 microg gestodene from day 17 to 28 of the cycle in a double-blind study. Placental protein P14 (PP14) and CA 125 concentrations in uterine flushing, endometrial morphology and irregular bleeding after 12 cycles of study were observed. Eleven and 12 women in the 25 and 50 microg groups respectively completed the study. There were no significant differences in pre-treatment biochemical and morphological indices between the groups. The median PP14 concentration increased from 332 to 5800 ng/ml (P < 0.001) and from 145 to 27 160 ng/ml (P < 0.001) in the 25 and 50 microg gestodene groups respectively. No between-group significant rise of PP14 was observed. Similarly, no significant change was seen between the initial and post-treatment concentrations of CA 125 for either group. All biopsies were atrophic at inception of the study, and both regimens produced secretory endometrial transformation in the majority of biopsies. No between-group difference was observed in the morphometric indices measured, or any significant correlation between the concentrations of PP14 or CA 125 and morphology. The mean number of days of withdrawal bleeding (3.8 and 4.2 days for 25 and 50 microg respectively) were similar. In conclusion, both regimens produced a significant rise in uterine flushing concentrations of PP14, but not CA 125. PP14 is a sensitive biochemical marker in the assessment of endometrial response to hormone replacement therapy.

Objective: Our purpose was to study combinations of estradiol and gestodene for prevention of bone loss in early postmenopausal women., Study Design: We randomly assigned 278 healthy, early postmenopausal women to receive either 2 mg 17beta-estradiol sequentially combined with 25 microg gestodene (group 2/25s), 2 mg estradiol sequentially combined with 50 microg gestodene (group 2/50s), 1 mg estradiol sequentially combined with 25 microg gestodene (group 1/25s), 1 mg estradiol continuously combined with 25 mg gestodene (group 1/25c), or placebo., Results: After 3 years the changes in bone mineral density of the spine were as follows (mean +/- SEM): group 2/25s, 7. 41% +/- 0.72%; group 2/50s, 8.53% +/- 0.90%; group 1.25s, 6.67% +/- 0.88%; group 1/25c, 4.44% +/- 0.59%; and placebo group, -2.03% +/- 0. 64%. The changes in bone mineral density were mirrored in the biochemical bone markers. The average responses for the urinary C-terminal telopeptide fragments of type I collagen corrected for creatinine excretion were as follows (mean of baseline +/- SEM): group 2/25s, -68.8% +/- 0.03%; group 2/50s, -72.8% +/- 0.02%; group 1/25s, -60.7% +/- 0.03%; group 1/25c, -52.28% +/- 0.04%; and placebo group, 6.5% +/- 0.09%. Beneficial lipid effects were found in all active groups. The decreases in low-density lipoprotein were as follows (mean +/- SEM): group 2/25s, -13.7% +/- 3.0%; group 2/50s, -14.6% +/- 3.2%; group 1/25s, -9.28% +/- 2.2%; group 1/25c, -9.92% +/- 2.4%; and placebo group, 1.53% +/- 1.9%., Conclusion: These results demonstrate that estradiol therapy with 1 mg estradiol is fully protective against early postmenopausal bone loss.

This was an open-label multicenter study to compare the cycle control and effect on well-being of two oral contraceptives containing gestodene and one containing desogestrel. A total of 2419 healthy women < or = 41 years of age were randomized to receive oral contraceptives containing monophasic gestodene (Minulet; n = 806, mean age 24.5 years), triphasic gestodene (Tri-Minulet; n = 808, mean age 24.6 years) or monophasic desogestrel (Mercilon; n = 805, mean age 24.6 years). Subjects were to participate in the study for up to 13 treatment cycles. A modified Moos Menstrual Distress Questionnaire was used to evaluate menstrual symptoms and to assess overall well-being. A total of 698 women were withdrawn from the study, 154 due to adverse events. Cycle control with gestodene was superior to that with desogestrel at almost all time points, particularly for breakthrough bleeding and/or spotting, which occurred significantly less frequently with gestodene than with desogestrel at cycles 1-7 and 9-11 (p < 0.05). Generally, the proportion of subjects with breakthrough bleeding and/or spotting was almost twice as great with desogestrel as with gestodene. The duration of bleeding was not consistently different between the gestodene and desogestrel groups; however, the intensity of bleeding was greater with gestodene at all time points (p < 0.05). The latent period before withdrawal bleeding was significantly longer for monophasic gestodene at cycles 1-5 and 8-10 (p < 0.05). Treatment significantly improved overall well-being at cycles 6 and 9 with triphasic gestodene and at cycle 13 with desogestrel; however, no statistically significant differences among treatment groups in overall well-being scores or individual factors of well-being could be identified. All three treatments were well tolerated. The most common drug-related adverse events were headache (14.2%), breast pain (6.2%), nausea (4.1%), metrorrhagia (3.9%) and abdominal pain (3.5%). The incidence of adverse events in all treatment groups was similar, with the exception of metrorrhagia, which occurred in more patients in the desogestrel group than in the gestodene treatment groups (p < 0.05).

Objective: To compare ovulation inhibition and ovarian activity with 21-day and 24-day regimens of a low-dose combined oral contraceptive (COC) containing 60 microg of gestodene and 15 microg of ethinyl estradiol., Design: Interventional observational study., Setting: Reproductive medicine unit., Patient(s): Fifty-eight healthy volunteers aged 18-35 years., Intervention(s): Ovarian activity was monitored every other day with the use of ultrasound to measure the diameters of follicle-like structures and blood samples to measure serum concentrations of 17beta-E2 and progesterone. Subjects were observed for five cycles: pretreatment and posttreatment control cycles and three cycles in which the COC was administered for either 21 or 24 days of each cycle., Main Outcome Measure(s): Occurrence of ovulation and evidence of ovarian activity., Result(s): The study was completed by 27 (90%) of the 30 subjects who received the 24-day regimen and by 24 (79%) of the 28 subjects who received the 21-day regimen. Ovulation was inhibited in all cycles in the 24-day group and in 74 of 75 cycles in the 21-day group. Luteinized unruptured follicles were seen in no cycles with the 24-day regimen and in 6 (8%) of 75 cycles with the 21-day regimen. Mean ovarian follicular development and serum 17beta-E2 and progesterone levels were lower in the 24-day group., Conclusion(s): The 24-day regimen is an innovative strategy for maintaining effective ovulation inhibition at ultra-low doses of contraceptive steroids.

Objective: The aim of the study was to assess the dose-response effects on the postmenopausal endometrium of 3 sequential combined hormone replacement regimens and 1 continuous combined hormone replacement regimen of estradiol and gestodene., Study Design: In this 2-year double-blind, placebo-controlled study, 278 healthy postmenopausal women received either 2 mg estradiol sequentially combined with 50 microg or 25 microg gestodene, 1 mg estradiol sequentially or continuously combined with 25 microg gestodene, or placebo., Results: All 4 hormone treatment regimens produced a safe endometrial histologic appearance. The regimens that were based on the lower dose of 1 mg estradiol was associated with less uterine bleeding than were those that were based on 2 mg estradiol. For sequentially opposing the 2 mg dose of estradiol, the dose of 25 microg gestodene was less efficient in producing secretory activity than was the dose of 50 microg gestodene. The measurement of placental protein 14 in serum reflected the secretory transformation of the endometrial buildup., Conclusion: The reduction in bleeding episodes associated with regimens with lower estradiol doses may lead to improved long-term therapy compliance by menopausal women. The potency of progestogens can be assessed by measuring the serum concentration of placental protein 14.

Cycle control and tolerability of two monophasic oral contraceptive pills containing 30 microg ethinyl estradiol (EE) with either 150 microg desogestrel (DSG) or 75 microg gestodene (GSD) were compared in women starting oral contraception. A minimum of 200 healthy women at risk for pregnancy were to be treated for a total of 6 cycles per patient in a prospective, randomized open parallel-group multicenter trial. Two hundred and forty-one subjects were randomized, 115 to DSG/EE and 126 to GSD/EE. Compliance to the study preparation was high (around 95%) in both groups and no pregnancies occurred during the study. Cycle control was excellent; there were no differences between the two groups with regard to incidence of spotting and breakthrough bleeding or duration and intensity of withdrawal bleeding. Side-effects were mild and in general comparable in the two groups. Both at baseline and during treatment, a higher proportion of women taking GSD/EE complained about breast tenderness. This resulted in more early withdrawals because of breast tenderness in the GSD/EE group. It was concluded that monophasic DSG/EE and GSD/EE are equally effective, have similar cycle control and both are generally well tolerated.

Research on the relationship between venous thromboembolism and the progestagen content of combined oral contraceptives has pointed to an increase in risk associated with products containing desogestrel and gestodene. Although many biases must have been at play in these nonexperimental studies, the errors that have been suggested and examined are not of a sufficient magnitude to account for the observed results. The most plausible explanation of the available data is that combined oral contraceptives containing desogestrel and gestodene carry a very small risk of venous thromboembolism, which exceeds the even smaller risk carried by products containing levonorgestrel. The position of norgestimate is uncertain.

An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile.

Objectives: To assess the effect of oral contraception started on the first day of menses and the fifth day following its onset, on women's compliance and the incidence of early breakthrough bleeding., Methods: Oral contraceptives (OCs) containing 30 micrograms ethinylestradiol and 75 micrograms gestodene were prescribed to 100 consecutive, healthy women for whom OCs were found to be the most suitable method of contraception. In the first 50 women, OCs were started on the first day of menses (day 1 group), while in the remaining 50 women, OCs were started on the fifth day after the onset of menses (day 5 group)., Results: The day 5 group had better compliance and a reduced incidence of breakthrough bleeding. No differences were observed between the two groups regarding age, parity and gravity., Conclusion: Starting an OC regimen should include initiation on the fifth day following the onset of menses. This regimen might increase patient compliance and lower the incidence of breakthrough bleeding.

Objective: The aim of the study was to investigate the endometrial histology and the bleeding pattern under a hormone replacement therapy regimen with continuous estrogen quarterly (3-monthly) combined with a progestogen., Methods: In a prospective, double-blind, randomised clinical trial, 30 healthy, postmenopausal women were allocated to one of the three trial preparations. Group I was treated with 1 mg micronized 17 beta-estradiol continuously, group II took 2 mg micronized 17 beta-estradiol continuously and group III took 1 mg and 2 mg 17 beta-estradiol alternating every 42 days (step-up regimen). One treatment cycle was 84 days, during the last 12 days estradiol was combined with 50 micrograms gestodene. The total treatment period comprised two cycles of 12 weeks each. With regard to endometrial histology, the second cycle was the actual study cycle. In each patient endometrial samples were obtained at the following time points: after the withdrawal bleeding in the beginning (day 8-11) of cycle II (Vabra-method), at the end of the estrogen mono-phase (day 70-72) of cycle II(Pipelle-method), and 8-11 days after cessation of all medication (Vabra-method). Histopathological classification was done by two experienced gynaecological pathologists. All patients kept record of their bleeding events in a diary. Analysis of variance and Kruskal-Wallis test were used for statistical analysis of the data., Results: 29 patients were evaluable for the assessment of endometrial histology. Only one sampling procedure (1.2%) yielded an insufficient amount of tissue. In each treatment group, simple (cystic) hyperplasia was observed exclusively at the end of the estrogen mono-phase (in total 4/29 patients, 14.8%). Hyperplasia disappeared in all cases after the combined estrogen-progestogen phase. No cytological atypia was seen. Fifty-five cycles were evaluable for the bleeding pattern. The onset of the scheduled bleeding (withdrawal bleeding) was in all cycles on day 11 of the combined phase or beyond. Unlike the duration, the severity of the scheduled bleeding episodes was estrogen-dose dependent. In the entire treatment period of 2 x 84 days, breakthrough bleeding occurred in 3 women, totalling 9 days. Spotting occurred rarely and was equally divided among the treatment groups., Conclusions: A quarterly sequential hormone replacement therapy regimen for women with anintact uterus gives rise to the development of simple hyperplasia without cytological atypia at the end of the unopposed estrogen phase. This occurs independent of the estrogen dose and can be reverted to inactive or atrophic endometrium by the addition of gestodene during 12 days. The combination offers good cycle control. The safety aspects should be investigated further in long-term studies before this regimen can be advocated for routine use.

Two triphasic oral contraceptives containing either gestodene or norethindrone as the progestogenic compound combined with ethinyl estradiol were compared in a randomized clinical trial to assess their contraceptive reliability, clinical tolerance and cycle control. Both preparations were effective in preventing pregnancy. The gestodene preparation proved significantly superior regarding cycle control and general tolerance.

The pharmacokinetics of gestodene (GEST) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 32 years) during a treatment period of three months with a new tri-step combination oral contraceptive (Milvane). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.1 mg GEST together with 0.03 mg EE2. There was a wash-out phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 18 h was observed for GEST. The total clearance was 0.9 ml x min-1 x kg-1 and the volume of distribution was 84 l. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged terminal half-life (20 to 22 h), reduced total (0.16 ml x min-1 x kg-1) and free clearance (ca. 27 ml x min-1 x kg-1), reduced volume of distribution (ca. 18 l). A concomitant EE2-induced increase in the SHBG concentrations by a factor of three as compared to pretreatment values was observed during a treatment cycle and appeared to be mainly responsible for the changes in the pharmacokinetics of GEST. Marked changes were also seen for the serum protein binding of GEST. After single dose administration, the free fraction of GEST was 1.3% and the fractions bound to SHBG and albumin were 69.4% and 29.3%, respectively. At the end of cycle one, the free fraction was only 0.6% and the fractions bound to SHBG and albumin were 81.4% and 18.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of GEST at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 299.2 and 278.1 pg x ml-1 x h, respectively, which corresponds to an about 30% increase as compared to single dose administration, where an AUC(0-4h) value of 216.1 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 36% and 60%, respectively, compared with the corresponding values measured prior to treatment. The fraction of unbound testosterone thus decreased from 0.5% to 0.3% during treatment.

The hypothalamo-pituitary axis in a group of 10 women (17-25 years of age) taking low-dose-estrogen oral contraceptives (20 micrograms ethinylestradiol (EE) + 150 micrograms desogestrel) for at least 6 months was investigated. The subjects underwent the GnRH (50 micrograms) and TRH (200 micrograms) stimulation tests for the evaluation of LH, FSH, Pr1, TSH and GH secretion. In the basal blood sample, E2, P, free T, A and SHBG levels were also determined. An elevation in LH response to GnRH was found, whereas FSH was inhibited. After TRH administration, the Pr1 response was the same in the oral contraceptive cycle as in the pretreatment cycle. Similar results were observed after TSH. Significantly, GH responded to TRH stimulation in the oral contraceptive cycles, but not in the pretreatment cycles. These results show that the new combination of 20 micrograms EE and desogestrel blocks hypothalamic production of GnRH. The different response to GnRH of LH and FSH reveals a differentiated sensitivity to the oral contraceptive which seems to inhibit the pituitary FSH-secreting gonadotrope cells in particular.

This study investigated the ability of a monophasic sub-50 oral contraceptive, containing desogestrel and ethinylestradiol, to postpone withdrawal bleeding in normal healthy women. In the analyzed group of 105 regular users of Marvelon, about 75% did not experience any vaginal bleeding during the 21 days of postponement. A 95% confidence interval was calculated which suggests that the percentage of women able to postpone their withdrawal bleeding successfully for 19 days ranges between 67.0% and 83.5%. Women with no vaginal blood loss in the postponement period were more willing to try this method of postponement again, compared to women who experienced vaginal blood loss in the postponement period. This difference was statistically significant. Nevertheless, the majority of women with vaginal blood loss were also willing to try this method again if necessary. The study results suggest that Marvelon offers an effective and acceptable method of postponing withdrawal bleeding for three weeks for most regular users of this contraceptive.

The effects of two oral contraceptive combinations either containing 0.020 mg ethynilestradiol (EE) + 0.150 mg desogestrel (Mercilon) or 0.030 mg EE + 0.150 mg desogestrel (Marvelon) were compared in two independent trials. Special attention was paid to serum levels of LH, FSH, prolactin, progesterone, testosterone, estradiol, SHBG in the first and efficacy, cycle control and tolerability in the second trial. The first trial included 71 women. Serum levels were determined in the cycle before treatment, in the third and sixth cycle of treatment and one cycle after treatment. The following difference was found: Women using the lower dosed preparation showed significantly less suppressed FSH values compared to women using Marvelon. Mean values of Estradiol and Progesterone were significantly suppressed 30% of our measurement in the lower dosed data sample showed extremely high Estradiol and Progesterone values. SHBG has increased by 200-300% and had no effect on prolactin and testosterone levels. In the second trial 781 women (5193 cycles) were evaluated. Assessment were made in the first, third and twelfth cycle of treatment. There were no marked differences between the two preparations with respect to normalisation of cycle length, bleeding duration and intensity. Differences occurred in frequencies of silent menstruation and breakthrough bleedings. They were more often by receiving 0.020 mg EE (7.7%, Mercilon) than with 0.030 mg EE (3.6%, Marvelon). With 0.020 mg EE a higher percentage of women showed body weight change. Blood pressure remained stable in both groups. Both preparations were very good tolerated with slightly more breast tenderness by taking 0.030 mg EE.(ABSTRACT TRUNCATED AT 250 WORDS)

Eleven healthy women used a contraceptive vaginal ring for three cycles. The rings released 15 micrograms of ethinylestradiol and 150 micrograms of 3-keto desogestrel per 24 hours. The rings were used for 21 days and then removed, rinsed in clean water and stored. After a 7-day ring-free period, the rings were reinserted. Totally, each ring was used for 3 cycles. The rings were well tolerated. The bleeding pattern was excellent. No woman showed any signs of ovulation when using the ring. Estradiol levels were suppressed, but showed an increase during the ring-free period as can be found during the pill-free period of an oral contraceptive regimen. When the ring was reinserted, the estradiol levels were rapidly suppressed again. SHBG capacity increased during use of the ring.

An association between an increase in the incidence of thromboembolic disease and the use of combined oral contraceptives has been shown by several epidemiologic studies. Evidence of the vascular complications of oral contraceptives suggests that venous thromboembolism correlates with estrogen dosage and arterial complications with both estrogen and progestogen components. In 60 healthy, randomly allocated women, the effects of ethinyl estradiol, 30 micrograms, combined with gestodene, 75 micrograms, and desogestrel, 150 micrograms, on blood coagulation, fibrinolysis, and platelet function were compared. Subjects were studied before oral contraceptive use, at 12, 24, 36, and 48 weeks of treatment, and at 6 and 12 weeks after treatment. Both oral contraceptives affected the hemostatic system, but our results indicate that the ethinyl estradiol/gestodene combination causes changes in the hemostatic system similar to those in the ethinyl estradiol/desogestrel combination. Factors VII and X activity were slightly higher with the ethinyl estradiol/desogestrel combination than with the ethinyl estradiol/gestodene combination, possibly reflecting a greater estrogenic effect.

Eight healthy women using one Silastic implant of 30 mm length filled with 3-keto desogestrel, the active metabolite of desogestrel, were studied for 36-664 days. The release rate of 3-keto desogestrel was quite constant and around 30 micrograms/day. No ovulations occurred. One woman was amenorrheic, while the others had different bleeding patterns, often with periods of spotting. No other side effects were recorded. The mean plasma levels of 3-keto desogestrel were 0.9 nmol/l after 1 month and 0.5 nmol/l after 12 months. 3-Keto desogestrel was less effective than testosterone, estradiol or levonorgestrel in displacing 3H-dihydrotestosterone from SHBG. It is concluded that contraception with 3-keto desogestrel delivered through an implant is a promising method for further investigation. With a single implant we found a duration of at least one year.

The purpose of this study was to evaluate the behavior of the hemostatic system during treatment with gestodene-containing oral contraceptives in monophasic (SHD 356, n = 15) and triphasic (SHD 415, n = 15) formulations. No changes in platelet (beta-thromboglobulin, platelet aggregate ratio, and megathrombocyte) and routine clotting assays were observed. Factor VIIc/factor VIIag ratio and fibrinopeptide A values showed a significant (p less than 0.005) increase after three cycles of both treatments. A slight, significant increase (p less than 0.01) in antithrombin III activity was observed during triphasic treatment. Protein C was unchanged. Fibrinolytic activity and plasminogen levels were significantly increased (p less than 0.05 and p less than 0.001). After 6 and 9 months, the factor VIIc/factor VIIag ratio was still significantly enhanced, whereas fibrinopeptide A values significantly (p less than 0.05) decreased, even if they were higher (p less than 0.05) than basal values. The persistence of factor VII activation without enhanced thrombin formation after long-term use of oral contraceptives suggests that at that time the activity of antithrombotic mechanisms counteracts the prothrombotic tendency, thus helping to minimize unwanted side effects on hemostasis during long-term drug administration.

Efforts to minimize oral contraceptive side effects have focused on the use of new dosage schemes and the synthesis of new steroids that can be used in safer, low-dose formulations. To determine whether the new progestogen gestodene offers an advantage in this regard, we studied its pharmacological and endocrine profiles. Gestodene was found to exhibit relative binding affinity and biological activity profiles similar to or better than those of progestogens in current use. Modulation by gestodene of luteinizing hormone-releasing hormone (LH-RH)-stimulated gonadotropin release in vitro and in vivo in a rat model system indicated that gestodene is some three times as biologically active as levonorgestrel. The borderline dose for inhibition of ovulation by gestodene was estimated in a total of 23 women with normal cycles. Levels of LH-RH, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were estimated during the ingestion of various doses of gestodene. A dose of 30 micrograms of gestodene caused inhibition of ovulation in 11 out of 12 subjects, and eight out of 11 showed follicular maturation. When 40 micrograms of gestodene was taken, six out of seven women did not ovulate, and one out of seven had a cycle with luteal insufficiency. These data indicate that 40 micrograms of gestodene is the borderline dose for inhibition of ovulation. A combination of 75 micrograms gestodene with 30 micrograms ethinyl estradiol was found to inhibit ovulation in ten subjects, and no follicular maturation was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Silastic capsules containing the synthetic progestin ST-1435 was inserted in 282 women of reproductive age who desired long-term contraception. Each woman received a single implant for 6 months' use. After evaluating the experience of the first 45 subjects, replacement capsules were offered to women desirous of continuing the method after the initial 6 months of use. In the first 6-month segment one pregnancy and 1720 woman-months of use were recorded. The total experience, through as many as six segments of use was 3373 woman-months of use and one pregnancy. The Pearl Index is 0.36 per 100 woman-years. The single pregnancy, recorded in the 1st month of the first segment, may represent a conception prior to implant placement. Amenorrhea was the most common side effect reported, with 83% of the women having at least one nonbleeding interval longer than 60 days during the first segment of use.

A well-known triphasic oral contraceptive (OC) containing ethinyl estradiol (EE) plus levonorgestrel (LNG) was compared with a triphasic containing the same dose of EE in combination with a 14% smaller dose of a new progestogen gestodene (GTD), in a prospective study of 24 and 20 healthy young women, respectively. Serial determinations of lipids, lipoproteins, and carrier proteins, and repeated standardized oral glucose tolerance tests (OGTTs) were conducted during 12 months of OC use. All lipid concentrations recorded before and during both treatments were strictly within the normal range. After 12 months, no significant fluctuations were observed in levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and apolipoprotein A1; concentrations of total triglycerides, phospholipids, and apolipoprotein B were slightly but significantly increased; the epidemiologically important ratios of HDL-cholesterol:total cholesterol and apolipoprotein A1:apolipoprotein B were not significantly changed, while the ratio of LDL-cholesterol:HDL-cholesterol was significantly decreased at 12 months of use of the GTD triphasic. SHBG levels (+ 100% over basal during use of the LNG-OC and + 200% with the GTD-OC) and transcortin (+ 100% over basal) increased early and remained stable. During use of the LNG-OC, glucose tolerance was strictly unchanged, while insulin response to a 75-g glucose load was transiently increased at 6 months (area under the curve [AUC] + 29%) before returning to normal at 12 months. During GTD-OC treatment, glucose tolerance was slightly impaired (AUC + 14%) at 6 months but back to normal at 12 months, while insulin response during OGTT was completely unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

The coagulation effects of oral contraceptives are determined by the interaction of the estrogen and the progestogen components. Serial studies on the coagulation system were carried out in 120 randomly allocated healthy women to compare the effects of (1) triphasic gestodene/ethinyl estradiol and triphasic levonorgestrel/ethinyl estradiol and (2) monophasic gestodene/ethinyl estradiol and monophasic desogestrel/ethinyl estradiol. The triphasic study showed significant increases in factor VII, factor X, fibrinogen, plasminogen, and fibrinolytic activity. No significant differences were noted between levonorgestrel and gestodene except for factor VII, which was higher with gestodene. Antithrombin III and anti-Xa were unchanged, and platelet aggregation was slightly accelerated with gestodene. The monophasic study is still in progress: Significant increases of factor VII, factor X, plasminogen, and fibrinolytic activity and no changes in antithrombin III, anti-Xa, and platelet aggregation have been found with both monophasic gestodene and desogestrel. The results of the triphasic study indicate that the effect of gestodene on the blood coagulation system is similar to that of levonorgestrel and that both formulations increase fibrinolytic activity. The increased coagulation activity would appear to be counteracted by enhanced fibrinolysis, so protecting the dynamic balance between coagulation and fibrinolysis. Further data are required in the monophasic gestodene and desogestrel study before any conclusions can be drawn.

The author reports the results of a prospective study of 10 women during six months use of an oral contraceptive combination with gestodene. Inhibition of ovarian function is showed by rapidly decreasing serum levels of estradiol and progesterone. Clinical and metabolic tolerance is excellent.

The pharmacodynamic effects of a new type of 3-keto-Desogestrel [3kDOG] releasing vaginal ring was studied in a group of 20 normally ovulating women during a period of 21 days continuous use. Peripheral blood samples were taken for the estimation of progesterone and oestradiol levels, ultrasound tracking for follicular growth and cervical mucus sampling for scoring [modified Insler] and sperm penetration testing during a control, treatment and recovery period. Additional blood samples were taken for the estimation of 3kDOG levels during the treatment period. After a control cycle, twenty normally ovulating women were selected and randomly divided into two groups. Group A were given a vaginal ring on day 5 of the menstrual cycle releasing 30 ug/24 hours of 3kDOG and group B a similar ring releasing 15 ug/24 hours of kDOG. Of the treatment cycles, none showed an ovulatory pattern in group A and there was only one in group B, the respective mean plasma levels of 3kDOG were 0.38 and 0.25 pmol/ml. The formation of "cysts" or persistent follicles was common to both groups, 6 out of 10 subjects in group A and 8 out of 10 subjects in group B had "cysts" greater than 25mm in diameter in the treatment cycle, this had become 5 out of 10 and 8 out of 10, respectively, in the recovery cycle. A comparison of the cervical mucus scores and sperm penetration of cervical mucus showed a significant reduction between the control and treatment groups but no significant difference between the two groups. The bleeding profiles showed an increase in percentage of bleeding days in both treatment groups to 25% in group A and 21.7% in group B [cf, 17.1%, 15.9%, respectively, in control month]; there being no statistical difference between groups. In conclusion, it is believed that given the efficacy demonstrated and the low level of menstrual disturbances found, this system warrants further investigation as a means of contraception as it appears to offer a better compromise than previous vaginal ring systems.

The in vitro and in vivo releases of norgestomet from hydrophilic implants were found to follow a matrix-controlled (Q - t1/2) process. The sorption of drug onto the implants was observed to obey the same mechanism but with a much smaller magnitide of the Q/t1/2 value. The effect of the extent of cross-linking on the magnitude of drug release (Q/t1/2) profiles was analyzed both theoretically and experimentally. The release of norgestomet from hydrophilic implants was found to be an energy-linked process. Two energy terms were calculated; the activation energy for matrix diffusion was 7.71 kcal/mole, and the heat of drug crystal solvation was 25-28.6 kcal/mole.