Second-generation Progestogens Research Articles

Control of side effects in strategy for increasing adherence to combined oral contraceptives. The role for a three-phase desogestrel-containing drug

Introduction. The frequency of side effects when taking combined oral contraceptives (COCs) is still high, which is the reason for refusal to take COCs by women worldwide with a frequency of 30 to 81 %. Management of side effects will help increase the user's adherence to the chosen method of contraception.Aim: to identify approaches to prevent users from refusing to take COCs due to side effects and increase adherence to their use.Materials and Мethods. The search for foreign literary sources in English was carried out in the international bases PubMed/MEDLINE, Google Scholar, Cochrane Library, in Russian in еLibrary database, by keywords: «hormonal contraception», «combined oral contraceptives», «side effects», «adherence». Search depth was 30 years (1992–2022). 437 and 74 articles were identified, respectively, of which the review included 44 manuscripts that satisfied the criteria for inclusion on the topic studied: full-text manuscripts with the results of original studies, systematic reviews and meta-analyses.Results. In the literature, there is a lower incidence of side effects of COCs containing 30–35 µg of ethinylestradiol (tri- and monophasic) compared with 20 micrograms of ethinylestradiol. It was found that the risk of intermenstrual bleeding is 30 % lower when using COCs containing thirdgeneration progestogens compared with second-generation progestogens (relative risk (RR) = 0.71; 95 % confidence interval (CI) = 0.55–0.91) using monophasic combinations as an example. The use of a three-phase COC containing desogestrel (DSG) was characterized by a low incidence of irregular bleeding (3.3 % in the first cycle and a decrease to 2.3 % by the 12th cycle), no effect on physiological parameters, a decrease in blood androgens content and a positive effect on seborrhea and acne, excellent tolerance (2.6% failures due to adverse events). Three-phase COCs are characterized by a lower frequency of intermenstrual bleeding (by 2 times) and amenorrhea (by 3 times) compared with other COCs. A positive effect on reducing the frequency of irregular spotting and breakthrough bleeding was shown when switching from a COC of another composition to a three-phase one containing DSG, and continuing to use it.Conclusion. A three-phase COC containing DSG continues to be a topical hormonal contraceptive for women both for the first time and when switching from another COC due to side effects, including those associated with menstrual irregularities.

Use of oral contraceptives in three European countries: a population-based multi-database study

ABSTRACTObjectives: The aim of the study was to assess the prevalence of oral contraceptive (OC) use, user characteristics and prescribing patterns by accessing health care databases of three European countries.Methods: A retrospective study was performed from 2009 to 2010 in three general practice (GP) databases from the Netherlands, UK and Italy and in one database of linked pharmacy and hospitalisation data in the Netherlands. The presence of selected chronic conditions and diagnoses of diseases associated with OC use were assessed, as were switches, discontinuations and types of OC used during the study period.Results: Among 2.16 million women aged 15 to 49 years, 16.0% were using an OC on 1 January 2010. The prevalence ranged from 19.7% in a Dutch database to 2.6% in the Italian database. During 2009 and 2010, mainly second-generation progestogens were prescribed in the Netherlands (79.4% and 78.3% of users), both second- (57.9%) and third-generation progestogens (43.6%) were prescribed in the UK, and mainly third-generation progestogens in Italy (61.8%). Most switches were to third- or fourth-generation pills. The prevalence of chronic diseases tended to be higher among OC users, and the proportions of women with a history of disease associated with OC use tended to be lower than among non-users.Conclusions: Second-generation OCs were most frequently prescribed in the Netherlands. In the UK, and even more so in Italy, many women used third- or fourth-generation OCs. Preparation switches were mainly to third- or fourth-generation OCs. Among OC users, a somewhat higher prevalence of chronic diseases was observed; however, information bias cannot be ruled out.

5B.1 Epidemiology of hormonal therapy related thrombosis

In this abstract some additional background data are provided for the presentation during the symposium. Venous and arterial thromboses have different risk factors [1] (see Table 1). There are single preparations that only contain a progestin or progestogen (progestogen-only contraceptives, POC), which also can be orally, subcutaneously, intramuscularly (depot) and intrauterinely (levonorgestrel containing IUD) administered. The levonorgestrel containing IUD acts predominantly locally. The contraceptive action is mainly due to the progestogen component by suppressing the luteinizing hormone (LH) that thus prevents the ovulation process. Nowadays the estrogen is added to the progestogen in order to avoid blood loss during the cycle (spotting and breakthrough bleeding), which often occurs in POCs or combination preparations with a very low estrogen content. Avoiding intermenstrual blood loss during hormonal contraception increases compliance and restrains pregnancy failure. Combination preparations are by far the most used. Since oral contraceptives first became licensed in 1959, the estrogen dose has been reduced. Early preparations contained 150mg mestranol or ethinylestradiol (EE2), the latter is currently used in virtually all combination preparations. Ethinylestradiol is a synthetic, slightly altered version of the naturally occurring estradiol, which is inactive when taken orally and becomes effective after the liver passage. The dose of EE2 has been stepwise reduced over the years, and nowadays most preparations contain 50mg (nearly used) or generally 30mg EE2, while some recently introduced brands hold even less, i.e. 20 or even 15mg EE2. The chemical composition of the progestogen content rather than the dose has also changed over time. In historical perspective three generations of progestogens have been categorized. Henzl and Edwards [6] provided the chemical base for this classification. Early preparations contained lynestrenol or norethynodrel, derivatives of norethindrone or nethisterone (testosterone like steroids) that are also known as first-generation progestogens or estranes, and are still used in short term (12 days) treatments, but not much in combined oral contraceptives anymore. Second-generation progestogens are gonanes, include norgestrel and levonorgestrel, of which levonorgestrel is widely used. Third-generation progestogens, which have the same basic steroid molecule as the gonanes, are desogestrel and gestodene. Both are also widely prescribed, despite their increased venous thrombogenicity [7], if combined with EE2. Finally, some progestogens are difficult to classify: norgestimate is categorized as a third-generation gonane, but because after uptake it is in part rapidly converted to levonorgestrel, it may metabolically belong among the second-generation progestogens. Two substances used in oral contraceptives in combination with an estrogen need to be treated separately, since they are not classified in a generation. First, cyproteronacetate (CPA; a gonane skeleton with extra carbons on the 17, 18 and 19 positions and designated as pregnane, consisting of in total 21 carbons) a derivative of progesterone, is also used for treatment of acne vulgaris, seborrhoea or mild hirsutism, however not more effective than other COCs [8 10]. Secondly, drospirenone (DRSP) is an anti-mineralocorticoid with anti-aldosterone effects [11,12). In combination with ethinylestradiol, CPA and DRSP have similar thrombogenic characteristics as thirdgeneration progestogens [13]. Finally, I mention the pregnanes, medroxyprogesteron used in depot form and the recently introduced chlormadinone acetate predominantly used in combination with EE2 [8,12].

Progestogens in combined oral contraceptives for contraception.

The progestogen component of oral contraceptives (OC) has undergone changes since it was first recognised that their chemical structures could influence the spectrum of minor adverse and beneficial effects. The major determinants of OCs are effectiveness, cycle control and common side effects. The rationale of this review is to provide a systematic comparison of OCs containing the progestogens currently in use worldwide. The objective of this review is to compare currently available low-dose OCs containing ethinyl estradiol and different progestogens in terms of contraceptive effectiveness, cycle control, side effects and continuation rates. The Cochrane Controlled Trials Register, MEDLINE and EMBASE databases have been searched systematically. Relevant pharmaceutical companies and the authors of articles included in this review have been contacted for clarification. Randomised trials reporting clinical outcomes were considered for inclusion. We excluded studies comparing mono- with multiphasic pills, and crossover trials with trials in which the difference in total content of ethinyl estradiol between preparations exceeded 105 micro g. The methodological quality and validity of studies were assessed based on the above-mentioned inclusion criteria. Both application of inclusion criteria and data extraction were performed independently by the reviewers. Results are expressed as relative risk (RR) with 95% confidence interval (CI) using a random-effects model. Twenty-two trials have been included in this review, thus generating 14 comparisons. Eighteen trials were sponsored by pharmaceutical companies and in only 5 cases had a blind trial been attempted. Most comparisons between different interventions included 1-3 trials. There was less discontinuation with second- compared to first-generation progestogens (RR: 0.79, 95% CI: 0.69-0.91). Cycle control appears to be better when using second- compared to first-generation progestogens for both mono- (RR: 0.69; 95% CI: 0.52-0.91) and triphasic (RR: 0.61; 95% CI: 0.43-0.85) preparations.Contraceptive effectiveness, spotting, breakthrough bleeding and the absence of withdrawal bleeding was similar when using GSD compared to LNG, although there was less intermenstrual bleeding in the GSD group (RR: 0.71, 95% CI: 0.55, 0.91). Drospirenone (DRSP) appeared to be similar to DSG. Based on data from one trial, compared to pills containing LNG, those containing GSD may be associated with less intermenstrual bleeding although they show similar patterns of spotting, breakthrough bleeding and the absence of withdrawal bleeds. GSD is also comparable to DSG. Regarding acceptability, all the indices show that third- and second-generation progestogens are preferred over first-generation preparations. Future research should focus on independently conducted, well-designed randomised trials that compare third- and second-generation progestogens in particular.

Effectiveness and acceptability of progestogens in combined oral contraceptives - a systematic review.

BackgroundThe progestogen component of oral contraceptives (OCs) has undergone changes since it was recognized that their chemical structure can influence the spectrum of minor adverse and beneficial effects.MethodsThe objective of this review was to evaluate currently available low-dose OCs containing ethinylestradiol and different progestogens in terms of contraceptive effectiveness, cycle control, side effects and continuation rates. The Cochrane Controlled Trials Register, MEDLINE and EMBASE databases were searched. Randomized trials reporting clinical outcomes were considered for inclusion and were assessed for methodological quality and validity.ResultsTwenty–two trials were included in the review. Eighteen were sponsored by pharmaceutical companies and in only 5 there was an attempt for blinding. Most comparisons between different interventions included one to three trials, involving usually less than 500 women. Discontinuation was less with second-generation progestogens compared to first–generation (RR 0.79; 95% CI 0.69–0.91). Cycle control appeared to be better with second-compared to first-generation progestogens for both, mono-and triphasic preparations (RR 0.69; 95% CI 0.52–0.91) and (RR 0.61; 95% CI 0.43–0.85), respectively. Intermenstrual bleeding was less with third- compared to second-generation pills (RR 0.71; 95% CI 0.55–0.91).Contraceptive effectiveness of gestodene (GSD) was comparable to that of levonorgestrel (LNG), and had similar pattern of spotting, breakthrough bleeding and absence of withdrawal bleeding). Drospirenone (DRSP) was similar compared to desogestrel (DSG) regarding contraceptive effectiveness, cycle control and side effects.ConclusionThe third- and second-generation progestogens are preferred over first generation in all indices of acceptability. Current evidence suggests that GSD is comparable to LNG in terms of contraceptive effectiveness and for most cycle control indices. GSD is also comparable to DSG. DRSP is comparable to DSG. Future research should focus on independently conducted well designed randomized trials comparing particularly the third- with second-generation progestogens.

Estrogens, progestogens and thrombosis

Hundreds of millions of women worldwide use either oral contraceptives or postmenopausal hormone replacement. The use of oral contraceptives leads to an increased risk of venous thrombosis, of myocardial infarction, of stroke and of peripheral artery disease, the risks of which are highest during the first year of use. Women with coagulation abnormalities have a higher risk of venous thrombosis when they use oral contraceptives (or postmenopausal hormones) than women without these abnormalities. The risk of venous thrombosis is also higher for preparations containing desogestrel or gestodene (third-generation progestogens) than for those containing levonorgestrel (second-generation progestogens). A previous thrombosis as well as obesity also increase the risk of oral contraceptive-related thrombosis. Hormone replacement therapy increases the risk of venous thrombosis, and has no beneficial, and possibly even a detrimental, effect on the risk of arterial disease. The risk of arterial disease in oral contraceptive users and users of hormone replacement therapy is at most weakly affected by the presence of prothrombotic abnormalities.

Biological coagulation findings in third-generation oral contraceptives.

An increased risk of venous thrombosis has been demonstrated in women receiving oral contraceptives (OCs). This risk has been primarily associated with the oestrogen content, but recent studies showed that the progestogen may also play a role. A higher risk was found with the so-called third-generation (desogestrel, gestodene) as compared with the second-generation progestogens (levonorgestrel). The risk was approximately two-fold. These unexpected results have been the subject of many debates, and bias--such as selection bias--has been suggested. The existence of bias cannot be completely excluded, but the thrombotic risk seems however to be slightly higher with the third-generation progestins. Haemostatic changes have been observed during OC intake. Both coagulation and fibrinolytic activity are increased: the beneficial profibrinolytic effect may counterbalance the deleterious procoagulant effect. This may explain that the absolute risk of venous thromboembolism is low during OC treatments. Some women who have pre-existing haemostatic abnormalities such as deficiency in antithrombin or activated protein C resistance with factor V Leiden, may be at a higher risk. The biological plausibility of the increased risk related to the third-generation progestogens has been explored. Theoretically, this could be due to an increased coagulation or to a lack of increased fibrinolysis as compared with second-generation progestogens. The only difference presently reported with third-generation OCs is a decreased sensitivity to activated protein C, possibly resulting in a hypercoagulability of greater magnitude. The selection bias suggested in epidemiological studies may also exist for the latter study, as women taking third- or second-generation OCs were not randomized. The possible increased risk related to third-generation OCs should not change the known general contra-indications. Practical guidelines are proposed for women with personal or family history of venous thromboembolism, and for those with a congenital cause of thrombophilia.

Effects of oral contraceptives on hemostasis and thrombosis

Objective: The object of the study was to determine the effects of oral contraceptives on blood coagulation, in particular on the protein C pathway. Study Design: Plasma samples from healthy men, from healthy female users and nonusers of oral contraceptives, and from heterozygous and homozygous male and female carriers of the factor V Leiden mutation (some of whom used oral contraceptives) were tested for their sensitivity to activated protein C by means of a new activated protein C resistance test developed in our laboratory. This assay is based on measurement of the effect of activated protein C on the endogenous thrombin potential, the time integral of thrombin generation initiated in plasma through the extrinsic coagulation pathway. Results: The normalized activated protein C sensitivity ratio ([ETP +APC /ETP –APC ] plasma / [ETP +APC /ETP –APC ] normal plasma , where ETP is endogenous thrombin potential, +APC is with activated protein C, and –APC is without activated protein C) of men was lower than that of healthy female nonusers of oral contraceptives. The normalized activated protein C sensitivity ratio of the users of oral contraceptives was significantly higher than that of nonusers of oral contraceptives. The normalized activated protein C sensitivity ratio of women who were using oral contraceptives with third-generation progestogens was higher than that of users of oral contraceptives with second-generation progestogens. Furthermore, the normalized activated protein C sensitivity ratio of 80% of the users of third-generation preparations fell within the 5th to 95th percentile of the normalized activated protein C sensitivity ratio of female carriers of factor V Leiden, a mutation that is associated with hereditary resistance to activated protein C and with an increased risk of venous thromboembolism. Conclusion: Acquired activated protein C resistance may explain the increased risk of venous thromboembolism among users of oral contraceptives reported in epidemiologic studies and the higher risk of venous thromboembolism among users of oral contraceptives with third- versus second-generation progestogens. (Am J Obstet Gynecol 1999;180:S375-82.)

Smoking and use of oral contraceptives: Impact on thrombotic diseases

Objectives: The study was intended to evaluate the effects of oral contraceptives and smoking on the risks of arterial and venous thromboembolic diseases among young women. Study Design: The study included a survey of data from published epidemiologic studies and evaluation of registry records of all Danish women discharged from the hospital from 1980 through 1993 after a first thromboembolic event. Questionnaires returned by survivors of such events and by control women during the period from 1994 through 1995 were analyzed. Results: In the 1980-1993 data the absolute risk of thrombotic diseases was seen to increase rapidly with age—exponentially for acute myocardial infarction or cerebral thromboembolic attack, linearly for venous thromboembolism—with risks of arterial diseases exceeding those of venous diseases. In the 1994-1995 data the relative risk of thrombotic diseases was seen to increase among users of oral contraceptives irrespective of age. Risk of venous thromboembolism (but not of acute myocardial infarction or cerebral thromboembolic attack) declined as duration of current oral contraceptive use lengthened, risk of acute myocardial infarction or cerebral thromboembolic attack was significantly decreased as ethinyl estradiol doses were reduced, and the relative risk (compared with nonusers of oral contraceptives) for arterial thromboembolic disease among users of desogestrel or gestodene (in conjunction with midrange or low doses of ethinyl estradiol) was lower than the relative risk among users of second-generation progestogens (in conjunction with midrange doses of ethinyl estradiol). The combination of smoking with oral contraceptive use may have a synergistic effect on risks of acute myocardial infarction and cerebral thromboembolic attack (but not of venous thromboembolism), particularly among users of high-dose (50 μg) ethinyl estradiol preparations. Conclusion: Among the formulations currently marketed in Denmark, where only the progestins desogestrel and gestodene are available with low-dose (20 μg) ethinyl estradiol (and only desogestrel was available in that form at the time of our studies), we prefer these third-generation oral contraceptives for smokers. We might also consider such oral contraceptives for women >35 years old as long as they had no other risk factors for thrombotic arterial diseases. (Am J Obstet Gynecol 1999;180:S357-63.)

Effects of progestogens on thrombosis and atherosclerosis.

In contrast with past practice, current hormone replacement usually includes a combination of oestrogens and progestogens. In this article, we review the effect of progestins on haemostasis and in the development of atherosclerosis. Second-generation progestogens produce minor haemostatic changes, and in lipid metabolism they decrease the synthesis of triglycerides and very low density lipoproteins (VLDL) and stimulate hepatic lipoprotein lipase. In combination, progestogens modify the effect of oestrogens on hepatic metabolism, endothelium and platelets. Several new progestins (known as third-generation) have less effect on lipid profiles. In vessel walls, animal studies have shown that progestogens are able dose-dependently to inhibit the beneficial effect of oestrogen without significant changes in lipid concentrations. The endothelium-dependent vasoconstrictor effect of progestogens on the arterial wall has been also evaluated. Large epidemiological studies show a two-fold increase in risk of venous thromboembolism with the use of third-generation progestins. Regarding the risk of myocardial infarction, no definite evidence is yet available with the use of third-generation progestins. The clinical consequence is therefore that second-generation progestins are the first choice in prescription for first-time users.

Thrombotic diseases in young women and the influence of oral contraceptives

OBJECTIVE: In the evaluation of the clinical impact of thrombotic diseases in young women, age-specific incidence rates must be calculated for both arterial and venous thrombotic diseases, but also the case-fatality rate and figures for the clinical consequences among those who survive thrombosis must be included. The aim of this analysis was to quantify the clinical impacts of both arterial and venous thrombotic diseases among young, nonpregnant women and thereafter to assess the influences of oral contraceptives on these measures.STUDY DESIGN: Nationwide register data on the morbidity and mortality of venous thromboembolism, myocardial infarction, and thrombotic stroke in Denmark, 1980-1993, and 3 ongoing case-control studies to assess the influence of oral contraceptives on the risk for development of these thrombotic diseases.RESULTS: In women 15-29 years old venous thromboembolism is about twice as common as arterial complications, whereas in women 30-44 years old the number of arterial complications exceeds that of venous diseases by about 50%. The mortality rate from arterial diseases is 3.5 times higher than that from venous diseases among women <30 years old and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability among women who had an arterial complication was about 30%; the proportion was about 5% among women with venous thromboembolism.CONCLUSION: Anticipating a differential influence on venous and arterial diseases from oral contraceptives with second- and third-generation progestogens, it was calculated that users of oral contraceptives with second-generation progestogens had 30% greater increased risk of thrombotic diseases, 260% greater increased risk of thrombotic deaths, and 220% greater increased risk of thrombotic disability than users of oral contraceptives with third-generation progestogens. (Am J Obstet Gynecol 1998;179:S62-7.)

Oral contraceptives and thrombosis.

The debate on whether the so-called third-generation progestogens (desogestrel, gestodene, and norgestimate) are associated with a higher risk of venous thrombosis than the older, so-called second-generation progestogens (principally levonorgestrel and norethindrone) continues. Much of the debate focuses on finding alternative explanations for the observed relationship. Alternative explanations include a prescribing bias, in which women at greater risk of venous thromboembolism were preferentially prescribed newer preparations; a failure by researchers to adjust adequately for residual confounding by age; and a failure by researchers to allow adequately for confounding by the duration of use of oral contraceptives. None of these explanations have been accepted without dispute, and the debate will clearly continue. A possible biologic explanation for the observed relationship of higher thrombosis risk with use of third-generation preparations has been put forward by Rosing et al. from Maastricht, who developed a new way of measuring activated protein C (APC) resistance. They found that users of third-generation preparations have higher acquired APC resistance than users of second-generation products. This finding requires confirmation.

Recent oral contraceptive use patterns in four European countries: evidence for selective prescribing of oral contraceptives containing third-generation progestogens.

A survey among oral contraceptive (OC) prescribers in the United Kingdom, Germany, Sweden and the Netherlands was performed to investigate OC prescription patterns before and after recent publicity in the media about studies reporting a higher risk of venous thromboembolism with OCs containing third-generation progestogens as compared to OCs containing second-generation progestogens. Before this publicity, most physicians prescribed third-generation OCs as their first-choice formulations for normal healthy women as well as for young girls (< 20 years) and older fertile women (30-35 years). In women presenting with cardiovascular risk factors, third-generation progestogens (desogestrel, gestodene) were considered safer and were five times more often prescribed than second-generation preparations (71% versus 14%). Most prescribers considered ethinylestradiol to be the most important component in relation to the risk of venous thromboembolism (71%), myocardial infarction (66%) and stroke (67%). In addition, for women presenting with cardiovascular risk factors, OC preparations containing 20 or 30 micrograms ethinylestradiol were considered safer than preparations containing 35 or 50 micrograms ethinylestradiol. Although the vast majority of prescribers (78%) stated that their attitudes towards safety of third-generation OCs had not changed since the recent publicity and the regulatory actions in some countries, 56% had changed their prescribing practice, largely due to patient concern about the safety of third-generation OCs. The results from this survey strongly suggest that, prior to the recent publicity, most prescribers considered third-generation OCs to be safer than second-generation preparations. Because of this perceived better safety profile, physicians have selectively been prescribing third-generation OCs to women at increased risk of cardiovascular disease. This pattern of selective OC prescribing may have seriously biased the results of the recently published studies on OCs and venous thromboembolism in favor of second-generation OCs.

Oral contraceptives and venous thromboembolism: An epidemiological review

New epidemiological studies have demonstrated a higher risk of venous thromboembolism among users of oral contraceptives (OCs) with third-generation progestogens desogestrel or gestodene compared with users of OCs with second-generation progestogens levonorgestrel or norgestrel. As the absolute risk of venous thromboembolism among users of OCs in general is lower in the new studies than in previously published studies, and as several important potential confounders are not controlled for in the new studies, the real difference in risk of venous thromboembolism between users of third- compared with second-generation products may be smaller than indicated in these new studies. At the same time, the risk of myocardial infarction may be smaller among users of third- compared with users of second-generation products. Until further epidemiological data emerge, it is therefore difficult to make general recommendations other than to use OCs with a low estrogen dose, and to make individual recommendations based on age, individual wish, and individual risk factors.

Oral contraceptives and venous thromboembolism: an epidemiological review

New epidemiological studies have demonstrated a higher risk of venous thromboembolism among users of oral contraceptives (OCs) with third-generation progestogens desogestrel or gestodene compared with users of OCs with second-generation progestogens levonorgestrel or norgestrel. As the absolute risk of venous thromboembolism among users of OCs in general is lower in the new studies than in previously published studies, and as several important potential confounders are not controlled for in the new studies, the real difference in risk of venous thromboembolism between users of third- compared with second-generation products may be smaller than indicated in these new studies. At the same time, the risk of myocardial infarction may be smaller among users of third- compared with users of second-generation products. Until further epidemiological data emerge, it is therefore difficult to make general recommendations other than to use OCs with a low estrogen dose, and to make individual recommendations based on age, individual wish, and individual risk factors.