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Abstract

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.

Keywords

bleeding pattern contraceptive efficacy extended regimen long-cycle treatment oral contraceptive suppression of menstruation

Until the beginning of the 20th century, women experienced much fewer menstruations than women do currently, as they had, on average, six live births or more, with a 3-year breast-feeding period for each [1]. In modern women, the increased number of ovulations and menstruations is associated with hormonal fluctuations and may be partly responsible for certain diseases such as endometriosis, uterine leiomyomas, premenopausal symptoms and ovarian cancer. Many women experience cycle-dependent complaints such as bloating, swelling, back pain, cramping and headaches, which in most cases can be reduced but not totally suppressed by conventional treatment with oral contraceptives (OCs) [2].

Treatment with OCs offers an effective method of reversible contraception. When it was introduced more than 40 years ago, the conventional regimen was developed to mimic the ovulatory cycle in order provide the illusion of natural cyclicity and fertility and to increase acceptance by society. Even currently, some women using OCs are not aware of the fact that withdrawal bleeding occurring during the hormone-free interval is iatrogenically induced and ‘artificial’ rather than ‘natural’.

High-dose progestogens have been prescribed by physicians for many years in order to postpone menstruation for medical and nonmedical reasons such as avoidance of bleeding during vacation, or during training or competition in sportswomen [3]. The omission of several hormone-free intervals reduces the number of withdrawal bleeds and is already commonly practised by physicians and patients, even though clinical research on long-cycle treatment has only been initiated in the last couple of years. This article evaluates the results of the trials on long-cycle OC regimens that have been published so far.

Attitudes towards menstruation

A survey carried out in The Netherlands revealed that the majority of women wished to have less frequent bleeding or amenorrhea, concerning both spontaneous menstruations and withdrawal bleeding during treatment with OC or hormone replacement therapy. In the 15–49 year-old age group, 55–60% of the women would prefer withdrawal bleeding either every 3 months or never during treatment with OCs, while 30–35% wished to bleed monthly [3]. A study of Australian women showed that 54% wished to have regular monthly bleeding, whereas 27% would prefer withdrawal bleeding every 3 months and 15% would prefer amenorrhea during treatment with OCs [4]. Similarly, women in Scotland, China and South Africa would prefer not to have regular withdrawal bleeding during treatment with OCs [5], whereas Brazilian women associated menstruation with femaleness, youth, fertility and health, and feared negative consequences of induced amenorrhea [6].

A representative survey carried out with 1195 German women of different age groups revealed that only 26–35% would prefer monthly bleeding, while 16–27% wished to bleed once every 3, 6 or 12 months, and 37–46% wished not to bleed at all [7]. The reasons for dislike of regular menstruation included fewer menstrual complaints, better hygiene, better quality of life (QoL) and less blood loss. Many women would suppress menstruation sporadically for personal reasons.

It has been reported that the majority of patients receiving OCs who were still experiencing cycle-dependent complaints would prefer a regimen of extended active pills with a shortened hormone-free interval, in order to reduce the frequency and severity of menses-associated symptoms [8].

Among the women who expressed a preference for regular withdrawal bleeding during the use of OCs, the main reasons were fear of pregnancy, infertility and adverse effects, and the opinion that menstruations were natural [7]. Regular withdrawal bleeding during the use of OCs mimics the normal ovulatory cycle and, therefore, reassures women that they are not pregnant. Even though this bleeding is iatrogenic, some women regard it as a natural process that reflects fertility and health. If menstruation is suppressed by continuous therapy, some women may fear that they have become infertile and are also anxious regarding pregnancy and adverse effects.

The uncertainty regarding the risks and objective benefits of long-term suppression of the menstrual cycle must be taken seriously, and potential negative psychological and sociological effects must be considered, particularly if OC-induced amenorrhea is used as a lifestyle choice. Conversely, beyond medical indications, the long-cycle regimen should be regarded as an option that allows individual women to choose the time and frequency of menstruations.

The attitudes and experiences of physicians with the suppression of menstruation and long-cycle regimens of OCs were investigated by means of a survey of 9000 German gynecologists. The response rate was 18% and 1152 questionnaires could be evaluated [7]. The results demonstrated that nearly all physicians had experience of the postponement of menstruation by OCs and 97% had prescribed a long-cycle regimen of OCs for a limited period of time. The reasons were medical indications (e.g., menstruation-related disorders or complaints, endometriosis, or polycystic ovary syndrome [PCOS]), increased contraceptive efficacy or request by the woman. The majority of the gynecologists preferred a regimen of continuous use of three packs of OCs without a hormone-free interval [7]. Regarding medical advice to patients, this might be a compromise to suppress bleeding only for a limited period of time, as no definite data on long-term risks are available.

A recently published US investigation revealed that nearly 90% of 551 healthcare providers surveyed thought that extended-cycle contraception should routinely be offered to patients with a need for hormonal contraception [9].

Long-cycle treatment/continuous therapy with contraceptives

The conventional regimen of hormonal orally, transdermally or vaginally administered contraceptive use mimics the natural cycles by inducing regular withdrawal bleeding caused by the drop of contraceptive steroid serum concentrations in the hormone-free interval. During the long-cycle treatment, women take two, three, four or even more packs of active pills (42, 63 or 84 tablets) continuously, generally followed by a hormone-free interval of 7 days. The extended regimen reduces the frequency of menstruations and cycle-related complaints. In principle, the duration of continuously taken active pills can be chosen arbitrarily, but since the packs usually contain 21 active tablets, the long-cycle regimens are mostly multiples of 21 days (Table 1) [4,7,8,10 –30]. In contrast to the long-cycle regimen, continuous therapy with OCs is characterized by a complete omission of hormone-free intervals (Figure 1).

Table 1.

Studies on long-cycle regimens of OCs.

Author (year)	Study type	Outcomes	Treatment*	Women (% dropouts)	Number of continuous OC days	Number of cycles	Ref.
Loudon et al. (1977)	Uncontrolled	Bleeding, adverse effects	EE 50/LYN 2.5	196 (44)	84	4	[4]
Hamerlynck et al. (1987)	Comparative	Bleeding	Tri-EE/LNG EE 30/LNG 150 EE 30/DG 150	34 37 29	41 42 42	1	[4]
De Voogd et al. (1991)	Uncontrolled	Bleeding	EE 30/DG 150	116 (9)	42	1	[4]
Kornaat et al. (1992)	Uncontrolled	Bleeding, adverse effects	EE 30/GSD 75	55 (2)	42	1	[4]
Cachrimanidou et al. (1993)	Randomized, controlled	Bleeding, adverse effects	EE 30/DG 150 EE 30/DG 150	198 (42) 96 (33)	63 21	5 13	[10]
Cachrimanidou et al. (1994)	Randomized, controlled	Hemostasis, lipid metabolism, SHBG, CBG	EE 30/DG 150 EE 30/DG 150	20 (35) 10 (30)	63 21	5 13	[11]
Kovacs et al. (1994)	Uncontrolled	Bleeding, adverse effects	EE 30/LNG 150	203 (71)	84	4	[12]
Coutinho et al. (1995)†	Controlled	Bleeding, adverse effects	EE 50/LNG 250 EE 50/LNG 250†	446 (14) 454 (14)	336 21	1 13	[4]
Ruchhoft et al. (1996)	Randomized, controlled	PCOS, hormone levels	EE 30/DG 150 EE 30/DG 150 GnRH-agonist	6 (33) 6 (0) 4 (0)	84 21 28	1 3 3	[13]
Sulak et al. (1997)	Experiences in practice	Therapy of hormone withdrawal symptoms	Various OCs	50 (26)	42–84	Variable	[14]
Miller & Notter (2001)	Randomized, controlled	Bleeding, adverse effects	EE 30/LNG 300 EE 30/LNG 300	46 (37) 44 (45)	42 21	6 12	[15]
Sulak et al. (2002)	Experiences in practice	Therapy of hormone withdrawal symptoms	Various OCs	267 (36)	42–84	Variable	[8]
Vercellini et al. (2002)	Randomized, comparative	Endometriosis-associated recurrent pelvic pain	EE 20/DG150 CPA 12.5	45 (20) 45 (13)	168 168	1 1	[16]
Kwiecin et al. (2003)	Randomized, controlled	Bleeding, adverse effects	EE 20/LNG 100 EE 20/LNG 100	16 (6) 16 (6)	168 21	1 6	[17]
Miller et al. (2003)	Randomized, controlled	Bleeding	EE 20/LNG 100 EE 20/LNG 100	39 (18) 40 (30)	336 21	1 12	[18]
Anderson and Hait (2003)	Randomized, controlled	Bleeding, adverse effects contraceptive efficacy	EE 30/LNG 150 EE 30/LNG 150	456 (41) 226 (29)	84 21	4 13	[19]
Wiegratz et al. (2004)	Experiences in practice	Bleeding	EE 30/DNG 2	30 (0)	189	1	[7]
Machado et al. (2004)	Uncontrolled	Bleeding, adverse effects, Hemostasis, lipid metabolism	EE 30/GSD 75	41 (22)	168	1	[20]
Archer et al. (2005)	Uncontrolled	Bleeding, adverse effects, contraceptive efficacy	EE 20/LNG 90	2134	273	1	[21]
Archer et al. (2005)	Uncontrolled	Ovarian activity	EE 20/LNG 90	58	84	1	[22]
Portman et al. (2005)	Uncontrolled	Bleeding, adverse effects	EE 30/LNG 150	189	84	8	[23]
LaGuardia et al. (2005)	Randomized, controlled	Bleeding	EE 20/NGMN 150 EE 20/NGMN 150	158 81	84 21	1 4	[24]
Anderson et al. (2005)	Uncontrolled	Endometrium	EE 30/LNG 150	50	84	4	[25]
Miller et al. (2005)†	Randomized, controlled	Bleeding, acceptance, endometrium	EE 15/ENG 120 EE 15/ENG 120 EE 15/ENG 120 EE 15/ENG 120	108 (23) 107 (28) 105 (38) 109 (36)	21 42 84 357	13 7 4 1	[26]
Foidart et al. (2006)	Uncontrolled	Bleeding, adverse effects, acceptance, endometrium	EE 30/DRSP 3	177 (19)	126	1	[27]
Anderson et al. (2006)	Uncontrolled	Bleeding, contraceptive efficacy, safety	EE 30/LNG 150 EE 10 (interval)	1006 (50)	84 7	4	[28]
Birtch et al. (2006)	Randomized, controlled, comparative	Endometrium, ovarian activity	EE 30/LNG 150 EE 30/LNG 150 EE 35/NGM 250 EE 35/NGM 250	8 9 8 11	21 84 21 84	3 1 3 1	[29]
Edelman et al. (2006)	Randomized, comparative	Bleeding, acceptance	EE 20/LNG 100 EE 30/LNG 100 EE 20/NETA 1 EE/30/NETA 1	36 (44) 34 (62) 33 (45) 36 (28)	180 180 180 180	1 1 1 1	[30]

Controlled: same preparation conventionally used; comparative: different preparation used.

Doses are given as μg, except NETA (1 mg), LYN (2.5 mg), DNG (2 mg) and DRSP (3 mg).

†

Tablets were administered intravaginally.

CBG: Corticosteroid-binding globulin; CPA: Cyproterone acetate; DG: Desogestrel; DNG: Dienogest; DRSP: Drospirenone; EE: Ethinylestradiol

ENG: Etonogestrel; GnRH: Gonadotropin-releasing hormone; GSD: Gestodene; LNG: Levonorgestrel; LYN: Lynestrenol; NETA: Norethisterone acetate; NGM: Norgestimate; NGMN: Norelgestromine; OC: Oral contraceptive; PCOS: Polycystic ovary syndrome; SHBG: Sex hormone-binding globulin; Tri-EE/LNG: Triphasic OC with EE und LNG.

Figure 1.

Different long-cycle regimens and continuous treatment of hormonal contraceptives.

Contraceptive efficacy

Compliance

The conventional regimen of low-dose monophasic OCs (21 active tablets followed by a 7-day hormone-free interval) reliably prevents unintended pregnancies, provided that the tablets are taken according to the instructions. The proportion of women who conceive while taking the preparation without error is very low (‘method failure’), and most of the unintended pregnancies are caused by missing tablets (‘user failure’). It has been demonstrated that compliance problems are common among all age groups, but especially in adolescents, with as many as 47% of women missing one or more pills/cycle, 22% missing two or more pills/cycle and, in high-risk adolescent groups, rates of unintended pregnancies of up to 18% were observed [31,32].

During the hormone-free interval of 7 days, increasing follicle-stimulating hormone levels cause follicular development as indicated by the rise in estradiol levels and the increasing number of follicles greater than 4 mm in diameter, which may ovulate [29,33 –35]. Missing pills immediately before and/or after the 7-day hormone-free interval prolongs the period without contraceptive steroids and puts women at the greatest risk of unintended conception [36].

By contrast, reducing the hormone-free period to 5 days has been shown to enhance the suppression of gonadotropins and decrease the probability of re-establishing follicular activity, even with very low doses of contraceptive steroids [33]. The lower the number of hormone-free days, the more pronounced this effect. This was demonstrated during the use of an ultralow-dose OC with ethinylestradiol (EE) 15 μg and gestodene 60 μg after shortening the hormone-free interval to 4 days [34].

As a consequence, the total omission of hormone-free days between two packs – the continuous OC-regimen – prevents the development of dominant follicles and breakthrough ovulation more effectively than the conventional regimen [29].

Even though the contraceptive efficacy of treatment with long-cycle regimens has not been found to be superior to that of the conventional use of OCs in clinical trials thus far [28,37], it can be assumed that the extended-cycle and continuous use of OCs provide a more pronounced contraceptive efficacy than the conventional regimen due to their enhanced suppression of gonadotropins and reduced follicular activity [22,33]. A randomized trial revealed that during long-cycle treatment (84 days) with a combination of EE 30 μg and levonorgestrel (LNG) 150 μg or norgestimate 250 μg, no dominant follicles developed, whereas during the conventional treatment with the same preparations (three cycles, 21 days each), eight dominant follicles and two ovulations were observed in 16 women [38]. The clinical data published so far may be strongly influenced by considerable compliance problems. A European randomized, multicenter trial revealed no pregnancies in 323 women treated continuously for 273 days with EE 20 μg and LNG 90 μg, whereas during conventional treatment with EE 20 μg plus LNG 100 μg over 13 cycles, three pregnancies occurred [39].

Contraceptive efficacy of OCs during concomitant use of drugs

Shortening of the pill-free interval has previously been recommended for women with suspected malabsorption or for patients who are receiving long-term enzyme-inducing drugs [36]. It is well known that concomitant treatment with certain drugs can reduce the contraceptive efficacy of OCs, either by inducing hepatic cytochrome P450-dependent enzymes (e.g., barbiturates or rifampicin) or by interrupting the enterohepatic circulation of EE by destroying the intestinal flora that hydrolyzes EE conjugates and allows reabsorption of free EE (e.g., antibiotics) [40].

As omission of the hormone-free interval has been found to cause a profound suppression of follicular development, continuous treatment with low-dose OCs may be an option for patients receiving long-term therapy with drugs that are known to reduce the efficacy of contraceptive steroids, rather than treatment with high-dose OCs, which may cause a higher rate of side effects.

It is known that in the case of enzyme induction caused by, for example, rifampicin or phenytoin, the reduction of serum levels of EE and progestogen does not exceed 50% [41,42]. Therefore, it can be assumed that the continuous use of OCs containing EE 30 μg during therapy with enzyme-inducing drugs may provide the same contraceptive effectiveness as the continuous treatment with ultralow-dose OCs or the progestogen-only pill. It has been previously recommended to shorten the pill-free interval to 4–5 days or to omit the pill-free interval for three cycles in the case of concomitant use of enzyme inducers [43]. However, it has to be kept in mind that there are no controlled studies on the contraceptive efficacy of extended treatment with OCs during the concomitant use of these drugs. However, this also holds true for the recommendation to use high-dose OCs in the case of concomitant therapy with interfering drugs.

Moreover, it has to be taken into account that the therapeutic effect of interfering medications, such as certain antiepileptic drugs, might also be altered during concomitant use of OCs.

Therapeutic use of extended-cycle regimens

Endometriosis

Endometriosis causes pelvic pain, dyspareunia, dysmenorrhea and infertility. The development of endometriotic lesions is estrogen dependent and suppression of ovarian steroid production leads to a regression of the lesions. Treatment with OCs may reduce the local estrogenic impact, as it reduces the level of ovarian estradiol synthesis and EE, the estrogen component of OCs, and has a less proliferative activity in comparison with estradiol [4].

Continuous treatment with EE 20 μg and desogestrel (DG) 150 μg for 6 months in patients with recurrent pelvic pain after surgery for symptomatic endometriosis caused a significant reduction of nonmenstrual pain, dyspareunia and dysmenorrhea, as well as an improvement in QoL and sexual satisfaction. The effect was similar to that of therapy with cyproterone acetate 12.5 mg/day, and two-thirds of the patients were satisfied or very satisfied after the treatment [16]. Moreover, it needs to be evaluated whether the symptoms of endometriosis that are suppressed during therapy with OCs recur after discontinuation of treatment. Although, in practice, many patients with endometriosis are continuously treated with OCs, further controlled studies are needed to assess the benefits of the extended-cycle treatment in those patients (Box 1).

Uterine leiomyomas

Even though most uterine leiomyomas are asymptomatic, they may cause pain, menorrhagia and infertility in a certain proportion of patients. Since the growth of uterine fibroids is estrogen dependent, it can be inhibited by treatment with gonadotropin-releasing hormone (GnRH) agonists and antagonists, androgens, progestogens or aromatase inhibitors, which suppress the synthesis of estradiol. It is known that the current use of OCs reduces the incidence of uterine leiomyomas and decreases the amount of menstrual blood-flow in those patients, while the hematocrit is increased [44,45].

During treatment with OCs, ovarian estradiol synthesis is suppressed, but in the hormone-free interval the estradiol level may rise. Even though there are no controlled studies on the use of long-cycle OCs in patients with uterine leiomyomas, it can be assumed that extended-cycle therapy with OCs may be superior in the treatment of symptomatic uterine leiomyomas as compared with the conventional regimen, since estradiol is permanently suppressed and the menstrual blood flow reduced. In contrast to therapy with GnRH analogs or antagonists, treatment with OCs does not lead to estrogen-deficiency symptoms such as enhanced bone resorption (Box 1).

Polycystic ovary syndrome

Continuous treatment with OCs causes a more pronounced suppression of ovarian androgen synthesis than the conventional regimen, which may result in an ameliorated effect on androgen-dependent symptoms such as acne, hirsutism and androgenetic hair loss [13]. It has been demonstrated that androgens, as well as luteinizing hormone (LH) levels, rise during the hormone-free interval, whereas continuous treatment with a combination of EE 30 μg and DG 150 μg for 3 months caused a significant reduction of LH and testosterone, which was comparable to the effect of monthly injections of a depot GnRH agonist [13].

It has to be taken into consideration, that there are not yet sufficient data on the long-term risks of OCs, neither for conventional nor extended-cycle regimens, in patients with PCOS, which is associated with various risk factors for cardiovascular disease. Therefore, a deleterious effect of OCs in those patients cannot be excluded (Box 1) [46].

Hemorrhagic diathesis

Patients with hemorrhagic diathesis caused by afibrinogenemia, factor XII, factor IX deficiency or von Willebrand's disease experience heavy bleeding during either natural menstruation or withdrawal bleeding with conventional use of OCs. The occurrence of intraperitoneal bleeding leading to a hemoperitoneum caused by ovulation has also been described. Since continuous treatment with OCs leads to a pronounced suppression of ovulation and regular withdrawal bleeding, there is no doubt that this therapy reduces blood loss, although there are no sufficient data from controlled studies so far. The severe menorrhagia of a young woman with afri-brinogenemia was stopped by continuous intake of EE 30 μg and LNG 150 μg [47].

Approximately 10% of young women suffer from iron deficiency due to prolonged and heavy bleeding and 2.2% of women have been diagnosed with iron-deficiency anemia [48,49]. It can be assumed that the extended-cycle regimen or continuous treatment with OCs will ameliorate the clinical situation and may be the therapy of choice after organic causes have been excluded (Box 1).

Cycle-dependent complaints

Migraine attacks that occur during the hormone-free interval under the conventional OC regimen are most probably caused by the fall in EE levels [50,51]. In such cases, the long-cycle regimen can significantly improve the clinical situation [10,15].

Up to 30% of fertile women suffer from premenstrual syndrome and experience symptoms such as depressive mood, irritability, breast tenderness, edema, headache and bloating in the late luteal phase. Changes in the serum levels of exogenous sex steroids, which occur during the hormone-free interval of conventional OC use, can induce similar symptoms in predisposed women. By contrast, continuous treatment with monophasic OCs for 6–12 weeks caused an improvement in 74% of patients suffering from hormone-withdrawal symptoms (Box 1) [2,14].

Safety of extended-cycles regimens

Compared with the conventional regimen, women ingest 25–34% more active pills during extended-cycle treatment, which at least theoretically might be associated with a higher rate of adverse effects. Conversely, it can be assumed that the daily dose rather than the total monthly dose is responsible for the development of adverse events during OC intake, since pharmacokinetic studies have demonstrated that during daily administration of OCs, a steady state of the serum levels of EE and the progestogen component is reached within 10 days. However, the long-term influence of extended-cycle therapy on the rate of severe adverse events has yet to be compared with that of conventional regimens.

Since the shortening of the hormone-free interval leads to a more pronounced suppression of follicular activity, long-cycle treatment with omission of the hormone-free interval most probably offers a higher contraceptive efficacy in compliant patients and, therefore, this regimen may even allow a reduction in the dose of the contraceptive hormones [21], which may then result in a further reduction of severe adverse events such as thrombosis.

Endometrium

It has been demonstrated that conventional treatment with OCs reduces the incidence of endometrial hyperplasia and cancer by 50–60%. The protective effect correlates with the duration of treatment [52].

As extended-cycle OC use leads to inactive and atrophic changes of the endometrium, the protection from the development of endometrial hyperplasia or cancer may be more pronounced [25,27,53].

Bleeding pattern

Multiple trials with extended-cycle regimens with various monophasic preparations and different EE/progestogen combinations (Table 1) revealed an elevated rate of breakthrough bleeding as well as spotting at the beginning of the treatment. Some of the published trials show a high proportion of drop-outs, mainly due to irregular bleeding [12]. During further treatment, the rate of irregular bleeding diminished, and after a few extended cycles it was similar to that under the conventional regimen [10,19].

In a German investigation of continuous treatment with EE 30 μg plus dienogest (DNG) 2 mg for 189 consecutive days, 50% of the women reported spotting during intake of the second pack – the time when withdrawal bleeding usually occurs. During further treatment, the rate of irregular bleeding was reduced to 10% [7].

Treatment with other preparations also caused breakthrough bleeding or spotting in more than half of the women when taken continuously for 6–12 months (13 packs of EE 20 μg and LNG 90 μg or six packs of EE 30 μg and drospirenone 3 mg) [21,27].

In comparison with the conventional regimen, the extended use of the contraceptive vaginal ring for 42, 84 or 364 days did not reduce the combined bleeding and spotting days, whereas long-cycle therapy with the contraceptive patch over 12 weeks significantly reduced the bleeding/spotting days when compared with the conventional treatment [24,26].

Most of the presented trials revealed a reduced number of bleeding days (withdrawal bleeding and irregular bleeding) during the extended-cycle regimen, while the incidence of spotting was equal or elevated in comparison with the conventional regimen [15,17 –19,37].

Women who have been treated with OCs according to the conventional regimen before the initiation of the extended-cycle reported a lower incidence of irregular bleeding than OC-naive patients [7,10].

The large differences in the composition of OC preparations, study design, duration of the long cycles and pretreatment with OCs makes it difficult to decide which combination might be advantageous with regard to the incidence of irregular bleeding during extended-cycle treatment. In a randomized, double-blind trial of the bleeding pattern during long-cycle OC regimens (180 days without hormone-free intervals), treatment with EE 20 or 30 μg plus norethisterone acetate 1 mg resulted in significantly less irregular bleeding and a higher level of satisfaction than the use of EE 20 or 30 μg plus LNG 100 μg. No significant difference was observed between preparations containing EE 20 or 30 μg [30].

It can be assumed that monophasic OCs that offer a good cycle control during conventional treatment are also suitable for long-cycle therapy.

Fertility after discontinuation

It is known that long-term therapy with OCs according to the conventional regimen does not lead to an impairment of fertility. Rather, a positive correlation has been found between the duration of previous treatment with OCs and improved fertility. A large, prospective study revealed that in women who used OCs for 2 years or less prior to discontinuation, the pregnancy rate was 50% lower than in women who were pre-treated with OCs for 5 years or longer [54]. It is not known whether this is due to a protective effect of OCs against pelvic inflammatory disease, endometriosis or other factors. In a prospective, observational study carried out in Germany, the cumulative pregnancy rates of 652 women after discontinuation of EE 30 μg and DNG 2 mg were 56, 82 and 94% after 3, 6 or 13 cycles, respectively, and corresponded with those observed in fertile couples who attempted to become pregnant without prior contraception [55].

A recently published study revealed that the time to first ovulation after discontinuation of OCs taken either conventionally for three cycles or continuously for 84 days was slightly prolonged to the same extent (+5 days) in both groups when compared with the natural cycle.

The available data suggest that the time to pregnancy after discontinuation of long-cycle OC use may be slightly prolonged, as is also observed during conventional therapy, but that long-term pregnancy rates are not reduced [29].

Adverse effects

In general, the results of clinical studies that compare the adverse effects of the same preparation taken either conventionally or according to a long-cycle regimen reveal no difference in the number or pattern of adverse events such as mas-talgia, acne, changes in bodyweight, nausea and depression [10,15,18,19]. In contrast, a lower incidence of headache during the long-cycle therapy has been observed, owing to the beneficial effect of continuously applied EE in those women who experience headache during the hormone-free interval [10,15,19].

Laboratory parameters

During treatment with OCs, steady-state EE levels are generally reached within 10 days of treatment, with peak serum levels that are 50–80% higher compared with the first day of treatment. Therefore, it can be assumed that EE levels should remain constant thereafter, regardless of whether active pills are taken for 21 days or longer [41,56].

In a randomized, controlled study, the effects on various metabolic parameters of long-cycle treatment with a combination of EE 30 μg and DG 150 μg for 12 months were compared with those of the conventional regimen of the same preparation. No significant differences were found between the two regimens with respect to the changes in various lipid and hemostasis parameters [11].

Similarly, no significant differences between conventional and extended-cycle regimens with regard to the effects on various metabolic parameters have been observed using other preparations [19,20].

Despite the fact that no significant differences have been found in hemostasis, or lipid or glucose metabolism between conventional or long-cycle treatment thus far, it must be emphasized that the available data are limited and that the clinical relevance of changes in surrogate parameters with regard to health risks remains an open question. Therefore, no definite conclusions can be drawn from those results.

Conclusion

Several investigations have revealed that women would prefer less frequent menstruations or amenorrhea to regular menses for several reasons. Treatment with OCs according to the long-cycle regimen allows the choice of the time of withdrawal bleeding, which may be an advantage with respect to leisure-time or occupational activities.

Extended-cycle therapy prevents cycle-dependent complaints such as dysmenorrhea and has beneficial effects in women who experience headache or migraine during the hormone-free interval with conventional OC use [57]. Moreover, the frequency and intensity of menstruations, as well as menses-associated complaints, are reduced.

Since the shortening of the hormone-free interval leads to a more pronounced suppression of ovarian follicular activity, it can be assumed that the omission of hormone-free intervals during long-cycle therapy increases the contraceptive efficacy, provided that compliance is not reduced. If the first pack has been taken correctly, omission of up to seven consecutive active pills will not result in a pregnancy rate higher than observed with the conventional OC regimen. Continuous treatment with OCs has also been recommended for patients who are concomitantly treated with drugs that are known to impair the efficacy of OCs [43].

In the first months of long-cycle treatment, irregular bleeding occurs more frequently than during conventional OC use, especially in first-time users of OCs. However, most women prefer long-cycle therapy due to the reduction of total bleeding days and complaints that are associated with ovulatory cycles and menstruation. In addition, extended-cycle OC use may offer beneficial effects and might be prescribed for therapeutic reasons in patients with hormone-dependent disease such as endometriosis or uterine leiomyoma, as well as in patients with hemorrhagic disease. The available data suggest that the iatrogenic amenorrhea during extended-cycle treatment is rapidly reversible and that follicular development begins soon after discontinuation of OC use.

During long-cycle treatment, women are exposed to a higher levels of hormones compared with the conventional regimen, which at least theoretically might increase the risk of health problems. However, it has been demonstrated that the adverse effects of OCs mainly depend on the daily dose, and a steady state of the contraceptive steroids is reached within 2 weeks of treatment with OCs according to the conventional regimen. Most of the hormone-induced changes in metabolic serum parameters are partly reversed during the hormone-free interval of 7 days and, therefore, some of those, for example, sex hormone-binding globulin, might reach a slightly higher level. So far, there are two studies on metabolic changes during long-cycle treatment, which did not find any significant difference between the conventional and extended regimen concerning changes in surrogate parameters.

To date, there are no epidemiological data to evaluate the long-term risk of long-cycle treatment with regard to cancer and cardiovascular disease.

Future perspective

When OCs were developed in the 1960s, the conventional regimen of 21 active pills followed by a hormone-free interval of 7 days was chosen to mimic the natural cycle. It was believed that this regimen increased the user acceptability for hormonal contraception since regular menstruations reflect fertility. However, there was no medical reason for regular monthly withdrawal bleedings. Even though physicians have already been prescribing extended-cycle OCs for the treatment of excessive blood loss, dysmenorrhea and other disorders for many years, this regimen was limited to few patients.

Several surveys revealed that the majority of women dislike regular monthly bleeding either with or without the use of OCs. Accordingly, an increasing number of studies on long-cycle OC use have been carried out. So far, there are very few countries that provide extended-cycle OC preparations, but it can be assumed that within the next few years, OC preparations for long-cycle regimens will be available all over the world. Since women prefer fewer menstruations, many of them will change from conventional to long-cycle therapy despite a higher rate of irregular bleeding, as the number of total bleeding days is reduced. It remains to be clarified which regimen (63/7; 84/7; or other) and which preparation offer the best tolerability and cycle control. Before long-cycle therapy is generally recommended, the available data on efficacy, adverse effects and health risks must be considered.

Executive summary

Attitude towards menstruation

Several investigations have demonstrated that many women of different age groups would prefer less frequent menstruation and withdrawal bleeding with the use of oral contraceptives (OCs).

Reasons for the dislike of regular menstruations are: less blood loss, fewer menstrual complaints, better hygiene and better quality of life.

The majority of patients receiving OCs who still experience cycle-dependent complaints would prefer a regimen of extended active pills.

Extended & continuous use of hormonal contraceptives

A survey carried out in Germany showed that nearly all physicians had already prescribed OCs according to the extended-cycle regimen to their patients.

Reasons for this regimen were: menstruation-related complaints, endometriosis, polycystic ovary syndrome (PCOS), concomitant use of enzyme-inducers and request by the woman.

A US study revealed that 90% of American healthcare providers thought that extended-cycle contraception should routinely be offered to patients with a need for hormonal contraception.

Different regimens

Long-cycle or extended regimen:

Women take two, three, four or even more packs of active pills (42, 63 or 84 tablets) continuously, generally followed by a pill-free interval of 7 days.

Continuous treatment:

Women take OCs continuously with a complete omission of pill-free intervals.

Some trials on extended-cycle treatment have been carried out with the contraceptive transdermal patch and the vaginal ring.

Contraceptive efficacy

Shortening of the hormone-free interval leads to a more pronounced suppression of follicular activity. Therefore, it can be assumed that the omission of hormone-free intervals increases the contraceptive efficacy.

In the case of concomitant use of enzyme-inducers, it is recommended to either shorten the hormone-free interval to 4 or 5 days or to omit the hormone-free interval for several cycles.

Therapeutic use of extended-cycle regimens

The extended-cycle treatment may be of therapeutic use in the case of hormone-dependent diseases such as endometriosis, uterine leiomyomas, PCOS and hemorrhagic disease, as well as in patients with cycle-dependent complaints.

Adverse events

The rate of irregular bleeding is slightly elevated during long-cycle regimens, especially at the beginning of treatment and in women who are not already receiving OCs, whereas the number of total bleeding days is reduced.

Long-term studies are necessary to investigate the long-term risks associated with extended-cycle treatment, particularly with regard to cardiovascular disease and cancer.

Fertility after discontinuation

The return to follicular activity after termination of long-cycle as well as conventional treatment with OCs is slightly prolonged, but there are no data on fertility after discontinuation of extended-cycles thus far.

Footnotes

Inka Wiegratz and Herbert Kuhl have received honoraria for lectures, consultancies and expert reports from Jenapharm GmbH & Co. KG (Germany) and carried out a metabolic study with the extended-cycle regimen of an oral contraceptive containing ethinylestradiol 30 μg and dienogest 2 mg.

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Extended and Continuous Use of Hormonal Contraceptives to Reduce Menstruation

Abstract

Keywords

Attitudes towards menstruation

Long-cycle treatment/continuous therapy with contraceptives

Contraceptive efficacy

Compliance

Contraceptive efficacy of OCs during concomitant use of drugs

Therapeutic use of extended-cycle regimens

Endometriosis

Uterine leiomyomas

Polycystic ovary syndrome

Hemorrhagic diathesis

Cycle-dependent complaints

Safety of extended-cycles regimens

Endometrium

Bleeding pattern

Fertility after discontinuation

Adverse effects

Laboratory parameters

Conclusion

Future perspective

Footnotes

References