Experts' view on the role of oestrogens in combined oral contraceptives: emphasis on oestetrol (E4).

Introduction: The evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety. Methods: Seven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views. Results: Ethinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health. Conclusion: Oestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Ovarian function during and after treatment with the new progestagen Org 30659.

OBJECTIVE: To evaluate ovarian function during 21 days of oral administration of different doses of Org 30659, a novel selective progestagenic steroid. DESIGN: Randomized, double-blind, dose-finding study. SETTINGS: Three centers in Austria, Sweden, and the United Kingdom. PARTICIPANTS: Eighty-one healthy women 19-40 years of age with regular ovulatory cycles. INTERVENTION: Daily oral administration of 0.060, 0.120, 0.180, or 0.240 mg of Org 30659, or 0.075 mg desogestrel (reference group), for 21 days. MAIN OUTCOME MEASURE(S): Once-daily measurements of follicular diameter and 17-beta estradiol, progesterone, FSH, and LH levels. RESULT(S): Daily treatment with Org 30659 for 21 days caused dose-dependent suppression of ovarian activity. No ovulation was observed in any study group. On average, ovulation returned 16.5 to 22.1 days after treatment. The effects of desogestrel, 0.075 mg, were similar to those of 0.060 and 0.120 mg of Org 30659. All doses were well tolerated, as shown by the type of side effects that occurred, the absence of an effect on physical and laboratory findings, and the low rate of study discontinuation. CONCLUSION(S): Daily oral administration of 0.060-0.240 mg of Org 30659 suppresses ovarian function to a level sufficient to inhibit ovulation. This effect is dose-dependent, and the suppressive effect is readily reversible at all doses tested. Org 30659 can thus be safely administered orally for 21 days to healthy female volunteers in a dosage of 0.060 mg/d to 0.240 mg/d.

Implanon contraceptive implants: effects on carbohydrate metabolism.

The objective of the study was to assess the possible differences in effects of Implanon and Norplant implants on carbohydrate metabolism. This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Oral glucose tolerance test (OGTT) was performed before implant insertion and at 6, 12, and 24 months after implant insertion. Glycosylated hemoglobin A(1)C was measured in fasting samples and plasma samples during OGTT were tested for glucose and insulin levels. There was a significant increase in the area under the curve for both glucose and insulin during OGTT within each group with increasing duration of use. However, there was no significant change in the fasting plasma glucose values. There was no significant difference in the carbohydrate parameters between the two groups during implant use, except for a minimal but statistically significant rise in fasting glycosylated hemoglobin A(1)C levels at 24 months in the Implanon group. Both implants appear to induce mild insulin resistance but no significant change in serum glucose levels. These alterations in carbohydrate metabolism should have no clinical significance in healthy women.

Effect of Implanon use on selected parameters of thyroid and adrenal function.

In this article, the effects of Implanon implant use on thyroid and adrenal function was compared with those of Norplant implants. In this 2-year open randomized study of 80 implant acceptors, we found that both implants may induce minimal changes in thyroid hormones and cortisol levels, possibly secondary to alterations in the respective binding globulins in the serum. These alterations in thyroid and adrenal function would have no clinical significance in healthy women. In the Norplant group, sex hormone-binding globulin levels decreased, whereas increased levels were found in the Implanon users at the end of 2 years. These findings lend support to the fact that etonogestrel, released from Implanon implants, is significantly less androgenic than levonorgestrel, released from the Norplant implants.

A pilot efficacy study with a single-rod contraceptive implant (Implanon) in 200 Indonesian women treated for < or = 4 years.

In this 4-year open-label, noncomparative, single-center pilot efficacy study, the contraceptive efficacy, safety, bleeding pattern and acceptability of Implanon was studied in 200 sexually active women of proven fertility in Indonesia. All subjects received the single-rod subdermal implant Implanon, which contains 68 mg etonogestrel (3-keto-desogestrel), with an initial release rate of 67 micrograms etonogestrel/day. Contraceptive efficacy was analyzed by calculation of the pregnancy rate, bleeding patterns were determined by the 90-day reference period method, and acceptability by the discontinuation rate. No in-treatment pregnancies were reported during 658.4 women-years of exposure, resulting in a Pearl Index of 0.0 (95% CI 0.0-0.6). The overall bleeding pattern was acceptable, with no discontinuations because of irregular bleeding. Incidence of irregular bleeding was highest during the first two reference periods and decreased thereafter. Amenorrhea was experienced by 7%-12% of subjects during years 1 and 2, by 5%-7% during year 3, and by 2%-5% during year 4, with one discontinuation because of amenorrhea. No clinically significant changes were reported for systolic and diastolic blood pressure, body mass index, and hemoglobin level. Three adverse experiences were related to treatment and resulted in discontinuation (two headaches and one dyspnea). One difficult implant removal was reported. In conclusion, this pilot efficacy study indicates that Implanon provides excellent contraceptive reliability and an acceptable bleeding pattern. Overall safety and acceptability are good, as suggested by the low incidence of adverse experiences and the low discontinuation rate.

The effects of Implanon on lipid metabolism in comparison with Norplant.

This open, randomized study was intended to assess the effects of the new single-rod contraceptive implant (Implanon) containing etonogestrel on lipid metabolism in Indonesian women, in comparison with the six-rod implant Norplant, containing levonorgestrel. The effects of both products were compared with a control group using an intrauterine device (IUD) over a 3-year period. A total of 135 healthy volunteers of childbearing potential, aged 22 to 41 years, were enrolled in Jakarta, Indonesia. Ninety volunteers were randomized to use Implanon (n = 45) or Norplant (n = 45), and a nonrandomized group of 45 Multiload Cu 250 IUD users served as a control. Serum concentrations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein AI, apolipoprotein AII, and apolipoprotein B were measured. The ratios of HDL cholesterol to total cholesterol, of HDL to LDL cholesterol, and of apolipoprotein AI to apolipoprotein B were determined. Lipid and lipoprotein determinations were done at screening and after 3, 6, 12, 18, 24 and 36 months. Contraceptive efficacy and insertion and removal times were also recorded. Mean changes from baseline in the lipid and apolipoprotein parameters, although occasionally statistically significant, were small in all groups (less than 1 standard deviation of the mean concentration at baseline) and clinically not significant. Statistically significant differences between the Implanon and Norplant groups were only occasionally observed. In both implant groups, total mean cholesterol, LDL cholesterol, and apolipoprotein AI concentrations tended to decrease during the study, but statistically significant changes from baseline were only occasionally observed, suggesting that drug-related factors are not involved. The mean ratios of HDL/total cholesterol and the HDL/LDL cholesterol showed very little change over time in both implant groups; slight and statistically nonsignificant increases were noted at most time points. Similar changes were seen in the group of IUD users. It can be concluded that changes from baseline in the lipid and apolipoprotein parameters tested were generally small and did not differ between Implanon and Norplant.

PIP: This open, randomized study was intended to assess the effects of the new single-rod contraceptive implant (Implanon) containing etonogestrel on lipid metabolism in Indonesian women, in comparison with the six-rod implant Norplant, containing levonorgestrel. The effects of both products were compared with a control group using an IUD over a 3-year period. A total of 135 healthy volunteers of childbearing potential, aged 22 to 41 years, were enrolled in Jakarta, Indonesia. 90 volunteers were randomized to use Implanon (n = 45) or Norplant (n = 45), and a nonrandomized group of 45 Multiload Cu 250 IUD users served as a control. Serum concentrations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein AI, apolipoprotein AII, and apolipoprotein B were measured. The ratios of HDL cholesterol to total cholesterol, of HDL to LDL cholesterol, and of apolipoprotein AI to apolipoprotein B were determined. Lipid and lipoprotein determinations were done at screening and after 3, 6, 12, 18, 24 and 36 months. Contraceptive efficacy and insertion and removal times were also recorded. Mean changes from baseline in the lipid and apolipoprotein parameters, although occasionally statistically significant, were small in all groups (less than 1 standard deviation of the mean concentration at baseline) and clinically not significant. Statistically significant differences between the Implanon and Norplant groups were only occasionally observed. In both implant groups, total mean cholesterol, LDL cholesterol, and apolipoprotein AI concentrations tended to decrease during the study, but statistically significant changes from baseline were only occasionally observed, suggesting that drug related factors are not involved. The mean ratios of HDL/total cholesterol and the HDL/LDL cholesterol showed very little change over time in both implant groups; slight and statistically nonsignificant increases were noted at most time points. Similar changes were seen in the group of IUD users. It can be concluded that changes from baseline in the lipid and apolipoprotein parameters tested were generally small and did not differ between Implanon and Norplant.

A 4-year pilot study on the efficacy and safety of Implanon, a single-rod hormonal contraceptive implant, in healthy women in Thailand.

OBJECTIVE: To investigate the contraceptive efficacy, safety and acceptability of a new single-rod, progestogen-only contraceptive implant (Implanon). METHODS: In an open, non-comparative pilot study, 100 healthy women received a contraceptive implant containing the progestogen etonogestrel (3-ketodesogestrel) for 2 years with an optional extension up to 4 years. RESULTS: Subjects were exposed to Implanon for 296.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding-spotting days was 10 and the median number of bleeding-spotting episodes was 2. Amenorrhea occurred in 24-39% of subject during the first 2 years and in about 20% in those who continued in the 3rd and 4th years. The most common drug-related adverse event was headache (7%). A slight increase in body mass index was observed. Only a few subjects discontinued treatment early, due to bleeding irregularities (6%) or amenorrhea (1%). The cumulative discontinuation rates were 13.4% after 2 years, 25.3% after 3 years and 28.0% after 4 years of use. Within 3 months of implant removal, six normal pregnancies occurred, indicating a rapid return of fertility. The average time taken for insertion of the implant was 0.5 min, compared with 2.5 min for removal. CONCLUSIONS: Implanon demonstrated excellent contraceptive efficacy and was well tolerated during up to 4 years of use. The vaginal bleeding pattern was variable and was characterized by relatively few bleeding events, but proved acceptable to most subjects. Because of its single-rod design, Implanon was quickly inserted and removed without complications.

A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 microgram desogestrel or 30 microgram levonorgestrel.

The effects of two progestogen-only pills containing either 75 microgram desogestrel (DSG) or 30 microgram levonorgestrel (LNG) on hemostasis were investigated in a double-blind, randomized, controlled study of seven treatment cycles in 78 healthy women. DSG reduced factor VII activity (p < 0.05) and prothrombin fragment 1+2 (p < 0.05) and increased protein S (p < 0.001). LNG reduced factor VII activity (p < 0.01) and plasminogen activity (p < 0.01) and increased tissue-plasminogen activator (t-PA) (p < 0.05). At the end of the post-treatment cycle with DSG, protein S (p < 0.01) and t-PA (p < 0.05) were increased and plasminogen activity was decreased (p < 0.05), whereas with LNG, t-PA was increased (p < 0.001) and prothrombin fragment 1+2 (p < 0.05) and plasminogen activity (p < 0.001) were decreased. Between-group comparisons revealed higher values for DSG regarding the anticoagulatory parameter protein S at cycle 7 (p < 0.01) and post-treatment assessments (p < 0.05), and the fibrinolytic parameter plasmin-antiplasmin complex was higher with DSG at cycle 7 (p < 0.05) and at post-treatment (p < 0.05). Both preparations had comparable and potentially favorable effects of hemostasis, and may offer suitable hormonal contraception to women with a personal or family history of venous thromboembolic diseases.

The combined oral contraceptive pill: what advice should we give when tablets are missed?

Despite more than 30 years' experience with the pill, being by far the most thoroughly studied drug ever, we must conclude that there still is a remarkable paucity of data that would allow us to assess unambiguously its margins of efficacy. The physiological studies on which we must rely encompass limited numbers of subjects and are unlikely to include sufficient representatives of the vulnerable minority of women that really matter. Even though we realise that this vulnerable minority is there, we still cannot do better than to hypothesise about their characteristics, let alone identify them in advance. This lack of knowledge has contributed to the existence of diverging views on how to advise the general population of pill takers about missed tablets. Against this background, we felt there was a need to make an inventory of the existing data and, subsequently, to incorporate them in advice that in our opinion is most appropriate in the current state of knowledge. We have come to the conclusion, in contrast to what is often held, that it is not the number of tablets missed, but rather the timing relative to the pill-free interval that determines the impact of noncompliance. We further conclude that shortening of the pill-free interval to five or six days could substantially improve the efficacy of the pill: at the low doses currently used in oral contraceptives the total steroid burden would not be substantially increased, while still allowing withdrawal bleeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of loading on the synthesis of proteoglycans in different layers of anatomically intact articular cartilage in vitro.

The anatomically intact articular cartilage (approximately equal to 2.5 cm2) of whole bovine sesamoid bones was cultured on its bone support. A load of 5 kg was applied intermittently at 0.3 Hz by a specially designed loading apparatus for 7 days. [35S]-sulfate was added during the last 17 h of the experiment. Loading induced a 40% increase in [35S]-sulfate incorporation into aggrecans and an almost 3-fold increase in the synthesis of small proteoglycans. The loading effects occurred mainly in the upper half of the articular cartilage. Samples left unloaded for 7 days and then loaded for 7 days likewise showed an increase in [35S]-sulfate incorporation compared with unloaded controls.

Binding and hydrolysis of 2-azido-ATP and 8-azido-ATP by isolated mitochondrial F1: characterisation of high-affinity binding sites.

The kinetic parameters for the hydrolysis by F1 of the photoreactive nucleotide analogue 2-azido-ATP were determined (Vmax, 105 U/mg F1; Km, 250 microM, in the presence of 1.0 mM SO2-3). In the absence of an activating anion, a non-linear relationship in a Lineweaver-Burk plot was found for the hydrolysis of 2-azido-ATP. The 2-azido-analogues of ATP and ADP proved to be good photoaffinity labels causing notable inactivation of the F1-ATPase activity upon irradiation at 360 nm. This inhibition was also used to demonstrate high-affinity binding of these analogues to a catalytic binding site on the F1. High-affinity binding proved to be an Mg2+-requiring process, occurring with both 2-azido-ATP and 2-azido-ADP but hardly or not occurring with 8-azido-AT(D)P. Covalent binding of 2-nitreno-ATP upon irradiation of F1 containing tightly bound [beta-32P]2-azido-ATP results in a proportional inhibition of ATPase activity, extrapolating to 0.92 mol of covalently bound label per mol of F1 needed for the complete inactivation of the enzyme. When the F1 was irradiated in the presence of excess [beta-32P]2-azido-AT(D)P, 3-4 mol of label were bound when the enzyme was fully inactivated. In all cases, all or most of the radioactivity was found on the beta subunits.