Effect of extended-cycle regimen with an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on bleeding patterns, safety, acceptance and contraceptive efficacy.

BACKGROUND: The present study compared the efficacy and safety of a combined oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year of treatment. STUDY DESIGN: In a phase III, randomized, prospective, open, two-arm, multicenter study, 1315 sexually active women (range, 18-40 years) were treated with EE/DNG either conventionally (21/7 days) or according to an extended-cycle regimen (84/7 days). Data were documented on volunteer diaries, and adverse events (AEs) were reported during five visits. RESULTS: In the extended-regimen group, the total number of days with bleeding progressively decreased over time, and overall, the volunteers had fewer numbers of days with bleeding/spotting compared to those treated conventionally. Intracyclic bleeding, on the other hand, was more frequent in the extended-cycle group, although its frequency considerably decreased over time. Both regimens offered reliable contraception, with an unadjusted Pearl Index of 0.489 for the conventional regimen and 0.495 for the extended regimen. The number of AEs was higher in the extended-cycle group, although the group differences tended to decrease over time. CONCLUSIONS: Extended-cycle use of EE/DNG was effective and mostly well tolerated, appearing to be a favorable option for women who need or wish to omit the pill-free interval.

Prescribing preferences and personal experience of female gynaecologists in Germany and Austria regarding use of extended-cycle oral contraceptives.

OBJECTIVES: To investigate prescribing preferences and personal experience of female gynaecologists with extended-cycle use of combined oral contraceptives (COCs) in Germany and Austria. METHODS: A questionnaire on prescribing patterns and personal experience with extended COC regimens was delivered to female gynaecologists practising in Germany and Austria. RESULTS: Of 2,500 delivered questionnaires, 1,113 were returned. After exclusion of 22 invalid questionnaires, the remaining 1,091 (43.6% of delivered questionnaires) remained eligible for analysis and were considered as the full analysis set (100%). Nearly all gynaecologists (97%) reported prescription of extended-cycle regimens to their patients, independent of their personal experience as users. The main medical reasons for prescription were cycle-related headache (93.8%), dysmenorrhoea (88.2%), cycle-related complaints (74.5%), and hypermenorrhoea (70.9%). In total, 863 gynaecologists had personally used COCs, 321 (37.2%) in extended-cycle regimen. The most commonly employed combinations were 30 µg ethinylestradiol (EE) + 2 mg dienogest (n = 114; 37.5%) and 30 µg EE + 3 mg drospirenone (n = 69; 22.7%). CONCLUSIONS: Although considered off-label use, extended-cycle use of COCs is widely prescribed and personally used by German and Austrian female gynaecologists. The lack of personal experience with extended-cycle use does not impair the prescribing habit of gynaecologists with regard to extended-cycle regimens.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on lipid metabolism during 1 year of conventional or extended-cycle use.

BACKGROUND: The effects of extended regimens of combined oral contraceptives (COC) on lipid parameters are largely unknown. The present study compared the effects of a COC containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year. STUDY DESIGN: Lipid parameters were measured in 59 women treated with EE/DNG either conventionally (21+7 days) or in extended-cycle regimen (84+7 days). Blood samples were taken in a control cycle and at 3 and 12 months of treatment. RESULTS: The mean levels of total cholesterol, HDL cholesterol and HDL(2) cholesterol underwent modest to moderate significant increases over time, while the significant increase in triglycerides and VLDL cholesterol was more pronounced with both regimens. LDL cholesterol decreased slightly in both regimen groups, whereas lipoprotein(a) was transiently decreased at 3 months only in the extended-cycle group. The changes reached a steady-state at latest at 3 months, but did not exceed the given normal ranges for any of the parameters. Notably, except for lipoprotein(a), the changes in mean lipid levels were not significantly different in the conventional and the extended-cycle regimen at 3 or 12 months of treatment. CONCLUSION: Use of EE/DNG in conventional or extended-cycle regimen resulted in comparable changes of lipid parameters.

[Long-cycle treatment in oral contraception]. / Langzyklus bei Ovulationshemmern.

Surveys show that most women desire a change in their menstrual pattern in the sense that they would prefer less menstruations or even amenorrhea. On this behalf, there is no difference between women having spontaneous natural cycles and women taking the pill. The main reasons are less menstrual bleedings, better hygienic conditions, a better quality of life and less blood loss. In women wanting regular monthly periods, the opinion is dominant that suppression of menstrual bleedings is "unnatural". It is therefore primordial to inform women that contraceptive safety is even increased in users following the long-cycle principal and that a fertility decrease has not to be feared. The benefit of the long-cycle OC is a reduction of the hormonal fluctuations induced by the pill-free interval with its consecutive somatic and mental symptoms, as well as an increased contraceptive safety. The following cycle- and menstruation-dependent symptoms as listed as an indication for the long-cycle use: Endometriosis, hypermenorrhea, dysmenorrhea, hemorrhagic diathesis, uterine fibroma, polyzystic ovary syndrome, migraine due to estrogen-deficiency in the pill-free interval as well as premenstrual syndrome.

[Oral contraception - doses and way of administration]. / Hormonale Kontrazeption - Dosierung und Verabreichungsformen.

Since the correlation between the amount of Ethinylestradiol (EE) and the thromboembolic risk has been recognized, the development of new oral contraceptives (OC) has been characterized by a constant lowering of the EE dosage. The consecutive decrease of ovulation inhibition has been compensated by the introduction of potent progestagens. Therefore, the contraceptive safety has been maintained in presence of less side-effects. The effect of ultra-low-dose OC on acne and seborrhea remains beneficial. The effect of ultra-low-dose OC on bone is contradictory. Because there are fundamental differences between Estradiol and EE, the thromboembolic risk is not decreased by the parenteral administration of EE. In users of the contraceptive patch, it is even increased. EE is not bound at SHBG. Because of its Ethinyl group, the inactivation of EE occurs slowly. Therefore, EE reaches the liver in a low but constant concentration where it modifies many estrogen-dependent hepatic parameters significantly. One of these is hemostasis. It is generally accepted that such changes are responsible for the increased thromboembolic risk of the contraceptive patch and vaginal ring. A reduction of the hormone-free interval of the pill to 5 or 4 days results in a complete suppression of the ovarian function, a reliable ovulation inhibition and an increase of the contraceptive efficacy in spite of a reduction of the EE dosage to 20 microg or 15 microg.

[Contraception in adolescence and perimenopause]. / Kontrazeption zu Beginn und Ende der fertilen Lebensphase.

The risk-benefit-ratio of hormonal contraception (OC) is positive in adolescents as well as in women over 40 years of age if some essential rules are respected. In adolescents, the acquirement of a normal peak bone mass has to be guaranteed by the use of the OC. The dosage of the OC has to be adapted individually to the basic hormonal situation. In women over 40, contraindications such as hypertension, obesity, smoking or dyslipidemia have to be actively excluded. In both groups of age, the risk of a correctly indicated OC is inferior to the risk of an unwanted pregnancy.

[Contraception in women with special problems]. / Kontrazeption bei Problemfällen.

Thromboembolic, cardiovascular and cerebrovascular events are age-dependent. They are extremely rare in young women. In contrast to the progestogen-only pills, oral contraceptives (OC) increase the risk of venous thrombosis. However, decisive ist the genetic predisposition. In healthy non-smokers of less than 35 years of age, the risk to suffer from a myocardial infarction or a cerebrovascular accident is not increased by OC. Risk factors play a major role in the etiology of cardiovascular diseases. A detailed personal and family history is therefore mandatory before OC are prescribed. Very rarely, blood pressure is increased by OC. Although the incidence of such an increase is very low, blood pressure has to be measured regularly in pill users. Inspite of a current opinion, weight increase is rare in OC users. It depends mainly on the individual predisposition. An increased water retention can be reduced by a combined OC containing a progestagen with an antimineralocorticoid activity. Changes in insulin and blood sugar induced by low-dose OC are minimal so that they have no clinical relevance. OC do not increase the incidence of diabetes. Adrenal and thyroid function are not influenced by OC, there is no increased incidence of prolactinomas. Asthma is no contraindication against OC. If there is a cycle-dependent aggravation of the disease, OC might be beneficial. OC have no side-effects on the eye or the ear. In women suffering from lupus erythematodes having no renal participation, no increased antiphospholipid-antibodies and showing a stable or inactive disease, low-dose OC might be used.

[Does hormonal contraception increase the risk for tumors?]. / Erhöht die hormonale Kontrazeption das Tumorrisiko?

A non-contraceptive benefit of oral hormonal contraceptives (OC) is a diminished risk for certain benign as well as malignant tumours, such as benign breast tumours, uterine fibroids and ovarian cysts. Endometriosis itself is not positively influenced by OC, but dysmenorrhea is decreased. Modern low-dose OC do not increase the risk of liver cell adenomata or carcinomata. OC do not influence melanoma. Modern data do not suggest an increased risk for breast carcinoma in OC users. Long-term use of OC leads to a decreased risk of endometrial and colorectal carcinomata. Cervical carcinoma is not influenced directly by OC, but probably indirectly through a change in sexual behaviour. There is no increase of vulvar or vaginal carcinoma, even after long-term use of OC.

Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters.

BACKGROUND: The study was conducted to investigate the effect of a combined oral contraceptive (COC) containing 30 mcg ethinylestradiol and 2 mg dienogest with two different regimens on various hemostasis variables. STUDY DESIGN: Hemostatic parameters were measured in 59 women treated with a monophasic COC containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or with an extended-cycle regimen (4 extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle or on Days 82-84 of the first and fourth extended cycle. RESULTS: After 3 and 12 months, significant increases in fibrinogen (20%), factor VII antigen (50-60%), factor VII activity (45%), activated factor VII (30-45%) and factor VIII activity (10-20%) occurred in both treatment regimens. In both groups, there was a small but significant decrease in the level and activity of antithrombin, a 20-25% decrease in total and free protein S and a 15-20% rise in the level and activity of protein C, but no significant change of the thrombin-antithrombin complex. A significant over-time rise by about 25% of prothrombin fragment 1+2 occurred only in the extended-cycle group, but this effect did not differ significantly from that observed during conventional treatment. Plasminogen was elevated by 50% in both groups, while tissue-plasminogen activator (t-PA) activity rose by 15% in the conventional group and by 25-30% in the extended-cycle group. In both groups, t-PA antigen was reduced by about 30% and plasminogen activator inhibitor-1 by 40-60%. The levels of the plasmin-antiplasmin complex rose by 30-40% and those of D-dimers by 20-55%. The prothrombin time was slightly increased and the activated partial thromboplastin time was slightly decreased. CONCLUSION: In general, these results were in agreement with those observed during treatment with other COCs. The study demonstrated that during conventional and extended-cycle treatment with EE/DNG, a steady-state in the effects on hemostasis variables was reached within 3 months, and that the effects observed after 3 and 12 months of treatment did not substantially differ between conventional and extended-cycle regimen.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use.

BACKGROUND: This study was conducted to investigate the effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters. STUDY DESIGN: Thyroid and androgen parameters were measured in 59 women treated with a monophasic combined oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or according to an extended-cycle regimen (four extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle, or on Days 82-84 of the first and fourth extended cycle. RESULTS: At both time points, the serum concentrations of thyroxine-binding globulin were elevated by about 65% in both treatment regimens. Likewise, both groups showed an increase in total triiodothyronine (T3) and total thyroxine (T4) by 30-40%, and no change in free T4. Until the 12th month of conventional treatment, the level of free T3 remained unchanged but decreased slightly during the extended-cycle regimen. In both groups there was a rise of sex hormone-binding globulin by 210-230% after 3 months and by 220-250% after 12 months. The levels of total testosterone were reduced by about 40% and those of free testosterone by 55-65% after 3 and 12 months. CONCLUSION: The results suggest that, during conventional and extended-cycle treatment with EE/DNG, a steady state in the effects on thyroid hormones and androgen parameters was reached within 3 months and that the changes in the various hormonal parameters did not substantially differ between conventional and extended-cycle regimen.

Metabolic and clinical effects of progestogens.

Synthetic progestogens differ not only in their hormonal potency, but also in their spectrum of hormonal activities. Beside their progestogenic and anti-oestrogenic effects, they may exert oestrogenic, androgenic, antiandrogenic, glucocorticoid and/or anti-mineralocorticoid activities. Consequently, progestogens may influence various metabolic parameters and modulate oestrogen-induced alterations in lipid metabolism, haemostasis, and various other factors. Progestogens with androgenic properties may counteract ethinyloestradiol (EE)-induced changes in lipoprotein metabolism, but do not cause atherosclerosis in the presence of EE. Oral contraceptives (OCs) containing androgenic progestogens which attenuate the EE-dependent changes in haemostasis, may be associated with a lower risk of venous thromboembolic disease than OCs whose progestogens have a less androgenic profile. Progestogens with androgenic activity may also antagonize oestrogen-induced alterations in various other hepatic proteins and modulate the effect of EE on growth factors. Progestogens with antiandrogenic activity may enhance the beneficial effect of EE in women with hyperandrogenic manifestations. Progestogens with glucocorticoid effects may increase procoagulatory activity in the vessel wall, while progestogens with anti-mineralocorticoid activity may reduce the aldosterone-induced water-retention in some women. For most women the differences in the hormonal pattern of progestogens used in OCs are without clinical relevance, but may be useful for women predisposed for the development of certain disorders.

Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest.

OBJECTIVE: To examine the conception rate after cessation of a combination of 30 microg ethinyl E2 and 2 mg dienogest (EE/DNG). DESIGN: Prospective observational study. SETTING: Population-based cohort in Germany. PATIENT(S): Women who wished to become pregnant after cessation of an oral contraceptive (EE/DNG). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception rate within 1 year after termination of EE/DNG and time to pregnancy. RESULT(S): After 1 year of follow-up, the cumulative pregnancy rate was 86.6% (full analysis set; n = 706). When all participants with complete data were analyzed (n = 652), the cumulative pregnancy rate was 94.0%. More than 15% of the patients conceived in each of the first three cycles after termination of EE/DNG; the mean time to pregnancy was 3.5 cycles. The preceding duration of treatment with EE/DNG did not influence the conception rate. Except in the youngest age group (16-18 years), a certain delay was observed in the other age groups. CONCLUSION(S): The present prospective study revealed only a slight delay in regaining fertility during the first three cycles after cessation of EE/DNG. Thereafter, the cumulative rate of conception did not differ from that observed in fertile women who attempted to become pregnant without prior contraception.

The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits--an attempt to interpret the Women's Health Initiative results.

The results of the two arms of the Women's Health Initiative (WHI) study allow a comparative assessment of the contribution of the progestogen component to the changes in risk of cardiovascular disease and cancer during treatment of postmenopausal women with conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). However, the high proportion of older and overweight or obese women compromises any conclusions, since we estimate that 50% of the women would have the metabolic syndrome. In overweight postmenopausal women with hyperinsulinemia, the risk of breast cancer is elevated and cannot be increased further by hormone replacement therapy (HRT). Therefore, the non-significant, but consistent reduction in breast cancer risk during treatment with CEE alone might be based on an improvement of hyperinsulinemia. The 24% increase in breast cancer risk in the CEE/MPA group can be regarded as an artifact due to very low numbers of breast cancer diagnoses in the placebo group of women who had received HRT prior to the WHI study. The elevated risk of venous thromboembolism and the transient increase in the risk of coronary heart disease (CHD) during treatment with CEE/MPA but not CEE alone suggests a direct effect of MPA on the vessel wall. MPA has been demonstrated to upregulate the thrombin receptor, the thrombin-induced production of tissue factor and procoagulatory activity in the vessel wall owing to its glucocorticoid activity. In contrast, CEE alone reduced non-significantly the risk of CHD in women aged 50-59 years, suggesting that primary prevention is possible if estrogen replacement therapy is initiated early. As clinical studies on the effect of different progestogens combined with estrogens are scarce, a possible superiority of progestogens other than MPA remains to be proven.

Extended and continuous use of hormonal contraceptives to reduce menstruation.

During the use of long-cycle regimens of monophasic oral contraceptives, the total number of bleeding and cycle-dependent complaints is considerably lower than during conventional treatment with oral contraceptives. Despite an initially higher rate of irregular bleeding, the majority of women prefer the long-cycle treatment since it may improve quality of life. As this regimen provides an enhanced ovarian suppression, it may prevent pregnancies, especially in noncompliant women or patients who are concomitantly treated with drugs that may impair the efficacy of oral contraceptives. Postponement or suppression of withdrawal bleeding also reduces menses-associated disorders such as menorrhagia and dysmenorrhea, and has beneficial effects in patients with hemorrhagic diathesis, endometriosis, uterine leiomyomas and polycystic ovary syndrome. Long-term studies are necessary to assess the impact of long-term use of extended regimens of oral contraceptives on safety, for example, the risk of cancer and cardiovascular disease, and on fertility after discontinuation of treatment.

Breast cancer risk in the WHI study: the problem of obesity.

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.

Long-cycle treatment with oral contraceptives.

The conventional regimen of oral contraceptive (OC) use mimics the natural cycles by causing regular withdrawal bleeding, which can be avoided by omission of the hormone-free interval of 7 days. Consequently, long-cycle regimens with continuous administration of OCs for 3 or 6 months followed by a hormone-free interval of 7 days may reduce the frequency of menstruations and cycle-dependent complaints. Surveys have revealed that, despite a higher rate of irregular bleeding, the majority of women prefer the long-cycle regimen to the conventional OC regimen with regular bleeds every 4 weeks because it may improve quality of life. As this regimen increases the contraceptive efficacy to a large degree, continuous treatment with OCs may prevent unintended pregnancies in women who miss a pill or are concomitantly treated with drugs that are able to impair the efficacy of OCs. Postponement of withdrawal bleeding may also reduce or prevent menses-associated disorders such as hypermenorrhoea and dysmenorrhoea, and have beneficial effects in patients with haemorrhagic diathesis, endometriosis, uterine leiomyoma and polycystic ovary syndrome. Continuous use of OCs prevents the cyclic fluctuations of serum levels of ethinylestradiol and progestogen and, hence, the cyclic variations of metabolic serum parameters. Although the long-cycle regimen is initially associated with an elevated rate of irregular bleeding, the total number of bleeding days that require sanitary product protection is lower than during conventional OC treatment. Many physicians tend to prescribe extended OC cycles for postponement of menstruation or reduction of frequency of regular bleeding. This review summarises and examines the available data on OC long-cycle regimens. The data suggest that the rate of treatment-related side effects with OCs according to the long-cycle regimen is similar to that of conventional OC regimens. However, clinical trials are necessary to assess the impact of long-term OC long cycles on safety, particularly the risk of cancer and cardiovascular disease, and fertility after discontinuation of treatment.

Progestogen therapies: differences in clinical effects?

A large number of estrogen/progestogen preparations are available for the treatment of estrogen-deficiency symptoms. These preparations differ in the route of administration, the type and dose of both the estrogen and progestogen. The only indication for the addition of a progestogen is endometrial protection, but, depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breast-epithelial proliferation and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis and mood) the effects of the estrogen component. Available progestogens differ largely in their hormonal pattern and, in addition to their progestogenic and antiestrogenic action on the endometrium, they can exert androgenic, antiandrogenic, glucocorticoid and/or antimineralocorticoid effects. There are no comprehensive trials comparing directly the modulating effects of the various progestogens, and clinical and epidemiological data do not allow a definite conclusion on the clinical relevance of differences between progestogens.