Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development Rabe T, Goeckenjan M, Ahrendt HJ, Crosignani PG Dinger JC, Mueck AO, Lohr PA, Creinin MD, Sabatini R Strowitzki T J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 58-129

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Wir freuen uns auf Sie! Oral Contraceptive Pills Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years of Oral Hormonal Contraceptive Development T. Rabe1, M. Goeckenjan1, H.-J. Ahrendt2, P. G. Crosignani3, J. C. Dinger4, A. O. Mueck5, P. A. Lohr6, M. D. Creinin6, R. Sabatini7, T. Strowitzki1

The first oral hormonal contraceptive Enovid™ (9.85 mg norethynodreland 0.15 mg )(G.D.Searle, US) was approved for contraception by the FDA in the US in 1959 but was never marketed by Searle for contraception. One year later Searle got approval for a lower dose product Enovid 5mg™ (5 mg norethinodrel and 75 µg mestranol) as a contraceptive pill. On the 1st of January 1961, Bayer HealthCare (then Schering) launched its first oral contracep- tive (brandname: Anovlar® by Schering) in , followed a few months later by the launch in West . In the beginning it was approved only on prescription for the “treatment of painful menstrual cycles” in married women until later the indication „contraception“ was added. Shortly after the introduction of the pill in severe cardiovascular side effects were observed in the UK for Enovid™. The development of different formulations of oral contraceptives with less and progestins was initiated. Furthermore, highly selective derivatives of were investigated to find products well tolerated and with a low profile of undesired side effects. New, preferably neutral products were developed taking into consideration the metabolic profile and safety aspects of cardiovascular disease and cancer, especially . Growing knowledge in the field of gene analysis and a deeper understanding of the regulatory changes in the coagulation system led to a discussion as to the influence of oral contraceptives on women having genetic risk factors for thrombophilia. The development of oral hormonal contraceptives during the past 50 years has been accompanied by the continued search for new products. Specific formulas have been analyzed not only to provide data on the safety and reliability of the contraceptive method, in addition to possible non-contraceptive benefits (i.e. regular menstrual cycles, improvement of vulgaris, and fewer premenstrual symptoms), but also to find new compounds and formulas intended to replace those at the end of their patent lifespan. Methods of Good Clinical Practice have been established and large-scale epidemiological studies initiated (i.e. Study of the Royal College of General Practitioners, 1974) [566]. Several general approaches to OC development can be followed. Synthetic or natural provide a reliable cycle control and prevent estrogen deficiency symptoms due to the decreased of endogenous estrogen from growth follicles. More selective, highly specific progestins have been developed with pharmacological properties similar to natural , some with antiandrogenic properties and suitable for transvaginal, transdermal, subdermal or intrauterine application. Furthermore, these new progestins produce fewer undesired effects on the breast and other reproduc- tive organs and exhibit low carcinogenicity. Various additives have been tested for their additional non-contraceptive benefits (i.e. iron, folate, DHEA) either by preventing certain undesired side effects of estrogens and progestins or by improving the general health status. Combinations of estrogen and progestin have evolved from monophasic to multiphasic formulations. Combination products require lower doses of and provide a clinical profile similar to the normal menstrual cycle. New regimens (21 + 7, 22 + 6, 24 + 4, 84 + 7) with and without placebo pills or continuous administration have been used to maintain the contraceptive of the higher dose products and to achieve a stable bleeding pattern at lower doses. To date only Ortho-McNeil, Bayer HealthCare, MSD and Pfizer have been able to afford scientific research in the field of contraception and develop new products. The loss of patent lawsuits on their part, however, has allowed for the production of generic alternatives of oral contraceptives by other companies thus making it difficult for them to continue research in this specific area due to lack of money. In this comprehensive review the development of oral hormonal contraceptive therapy is analyzed step-by-step considering the rationale behind the development of individual substances, combinations, and the regimens developed for their application. J Reproduktionsmed Endokrinol 2011 (Spe- cial Issue 1): 58–128.

Key words: oral , side effects, non-contraceptive benefits, dose reduction, cancer, ethinyl , progestins, regimen

Please refer to the local summary of product characteristics and prescribing information.

 1. Introduction two women: Margaret Sanger, a nurse, months led to an anovulatory pseudo– and Katherine McCormick, a philan- [548]. The use of orally Combined oral hormonal contraceptives thropic millionaire, interested in the highly active progestins in combination – a combination of an oral active proges- women’s movement. Together, Sanger with mestranol allowed the break– tin necessary for inhibition and McCormick convinced Dr. Gregory through in OC development. Norethin- and an estrogen to guarantee cycle con- Pincus [519] to develop the pill [484]. drone was the first orally highly active trol – often referred to as the birth-con- progestin synthesized by the chemists trol pill or simply “the Pill”, were intro- Previous studies with continuous, gradu- , Luis Miramontes, and duced into general clinical use in the ally increasing dosages of natural pro- at Syntex in early 1960s. The development of the pill gesterone (50–300 mg/day) and diethyl- City in 1951 [157, 156]. One would not have been possible without (5–30 mg/day) over three year later at Searle in Skokie, Illinois,

Received and accepted: August 8, 2011 From the 1University Women’s Hospital Heidelberg, the 2Center for Gynecology and Clinical Research, Magdeburg, Germany, the 3 Granda Foundation Maggiore Policlinico Hospital, Milano, Italy, the 4Berlin Center for Epidemiology and Health Research, ZEG Berlin, the 5University Women’s Hospital, Tübingen, Germany, the 6University of Pitts- burgh, USA, and the 7University of Bari, Italy. Correspondence: Thomas Rabe MD, PhD, MD (hons.), Professor Obstetrics and Gynecology, Department of Gynecological Endocrinology and Reproductive Medicine, Univer- sity Women’s Hospital, Medical School Heidelberg, D-69115 Heidelberg, Voßstraße 9; e-mail: [email protected]

58 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Oral Contraceptive Pills the steroid chemist Frank B. Colton syn- common modern method in the devel- latory changes in the coagulation system thesized two more orally highly active oping countries [669]. Usage varies led to discussions about a genetic risk progestins, norethynodrel (an isomer of widely from region to region [668] and profile for thrombophilia and the need to norethindrone) in 1952, and norethan- according to age, education, and mari- preselect patients at risk. drolone in 1953 [114]. tal status. In some countries in Western Europe, more than 30% of the women Certain aspects of OC development are The first oral hormonal contraceptive of reproductive age are reported to be to be considered: Enovid™ containing 9.85 mg norethy- currently using an oral contraceptive nodrel and 0.15 mg mestranol method such as a COC. In Germany Substances: (G.D.Searle, US) had been approved for 53% of all women of reproductive age – Estrogens: synthetic or natural estro- contraception by the FDA in the US in (16,6 million) use contraceptives, 37% gens have been chosen which provide 1959 but was never marketed by Searle of whom use hormonal contraceptives a good cycle control and prevent for this indication. The same product had and 31,3% oral hormonal contracep- estrogen deficiency symptoms due to been previously approved in 1957 for tives, compared to only 1% of women low secretion of endogenous estro- treatment of menstrual disorders. in using oral contraceptives gens as a consequence of inhibition of [237]. follicular growth. A product with less progestin (5 mg – Progestins: more selective, highly norethindrone) and less estrogen (75 µg More than 100 million women world- specific progestins have been devel- mestranol) named Enovid 5mg™ by wide use oral hormonal contraceptives oped with pharmacological proper- Searle got FDA approval one year (June [640]. A study by Cogliano et al. in ties similar to natural progesterone, 23rd, 1960) later as a contraceptive pill 2005 [104], showed that since the intro- some with antiandrogenic properties and was available on the market by duction of oral contraception in the early making them highly potent and suit- August 18th, 1960 as the first oral contra- 1960s more than 300 million women able for transdermal (i.e. patch), in- ceptive pill. were thought to have used it until that trauterine, transvaginal or subdermal date, often for prolonged periods and applications. Furthermore, these pro- On January 1st, 1961, Bayer HealthCare without health problems. ducts should exhibit no carcinogeni- (then Schering) launched its first oral city nor have undesired cardiovascu- contraceptive (brand name: Anovlar® The development of oral hormonal con- lar side effects or adverse effects on by Schering) (4 mg ac- traceptives during the past 50 years has the breast and other reproductive or- etate and 50 µg EE) in Australia, fol- been accompanied by a search for new gans. lowed a few months later with the products and regimens driven not only – Additives: various supplements have launch in West Germany. The new for- by the intention to provide safe and reli- been tested to add some additional mulation based on the clinical trials able contraception while offering, in ad- non-contraceptive benefits and/or with norethisterone and varying dition, certain non-contraceptive ben- prevent undesired side effects of amounts of estrogens performed by efits (i.e. regular menstrual cycles, im- estrogens and progestins. the Belgian gynecologist Ferdinand provement of acne vulgaris, dysme- – Combinations: various monophasic Peeters (1960) [506] showed a higher norrhea and less premenstrual symp- and multiphasic OCs have been de- contraceptive efficacy and fewer side toms), but also to find new compounds veloped combining estrogen and effects [457]. Initially Anovlar® was ap- and formulas intended to replace those at progestins to the normal menstrual proved only on prescription for the the end of their patent lifespan. Methods cycle, progestin to find combinations “treatment of painful menstrual cycles” of Good Clinical Practice have been es- which allow lower effective doses of in married women. The package insert tablished and large scale epidemiologi- steroids and provide a similar clinical mentioned that during the “treatment cal studies initiated (i.e. Study of the profile. course”, ovulation would not occur. Royal College of General Practitioners, – Regimen: new regimens (22 + 6, 24 + Contraception was a , not an 1974 [566]). 4 [with and without placebo pills]) or indication [484]. Contraception was a continuous administration have been novel idea to the European woman and Upon introduction of the pill in Europe used to maintain the contraceptive ef- the pill met a market that was quite un- severe cardiovascular side effects were ficacy of the higher dose products and prepared. It took some time until the in- observed in the UK [356] and the devel- to achieve a stable bleeding pattern dication “contraception” was finally opment of products with less estrogen during the administration of low dose added to Anovlar. and progestins was initiated aimed at formulations. finding more selective and neutral for- According to United Nations’ estimates mulations which could be used in lower To date only Ortho-McNeil, Bayer of contraceptive prevalence among wo- doses in order to increase the tolerance HealthCare, MSD and Pfizer have been men of reproductive age, the pill is be- of COCs and to decrease the incidence able to afford scientific research in the ing used in 2011 by approximately 9% of undesired side effects. The safety as- field of contraception and develop new of women worldwide [324]. It repre- pects with regard to cardiovascular dis- products. The loss of patent lawsuits on sents the most common modern contra- ease and cancer, especially breast can- their part, however, has allowed for the ceptive method (including both revers- cer, caused worldwide concerns. Grow- production of generic alternatives of oral ible and nonreversible methods) in the ing knowledge in the field of genetics contraceptives by other companies thus developed countries and the third most and increased understanding of the regu- making it difficult for them to continue

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 59 Oral Contraceptive Pills research in this specific area due to lack men in the study is needed, as well as age 2,7 pills per cycle [2]. One group of money. the number of and the of women neglected to resume taking In the following paper the development reason for leaving the study (preg- the pill correctly after the pill free in- of oral hormonal contraceptives is nancy or other reasons). The Pearl In- terval (18% forgot the first ; an- analyzed looking at the rationale behind dex can be calculated using two me- other 24% forgot a tablet during the the development of various substances, thods: first week) (CORALIANCE-Study) combinations applied regimens. ● the number of pregnancies in the (n = 3316) [29]. Reviews on the history and some aspects study is divided by the number of – User’s negligence/prolonged pill– of the state of art of combined oral con- months of exposure, and then mul- free interval: delay in starting the traceptives can be also found using tiplied by 1200. next packet of active pills (i.e., ex- Wikipedia: “combined oral contracep- ● the number of pregnancies in the tending the pill-free, inactive or pla- tive pill” [270]. study is divided by the number of cebo pill period beyond 7 days), menstrual cycles experienced by – Intestinal malabsorption of active  2. Combinations and the women in the study, and then pills due to vomiting or diarrhea, multiplied by 1300. 1300 instead – interactions with active pills Regimen Options of Oral of 1200 is used on the basis that the that decrease contraceptive estrogen Contraceptives in view of length of the average menstrual or levels. Efficacy and Adverse cycle is 28 days, or 13 cycles per A comprehensive analysis done by Events year. Dinger et al. (2009) [155] as one part of Each method of birth control has two the EURAS-OC-study in 112,659 wo- In the first part of this chapter the influ- Pearl index numbers: men-years of exposure and 545 un- ence of OC combinations, regimens, and ● Method effectiveness: the Pearl in- planned pregnancies showed that the po- dosages on contraceptive efficacy is dex number for use under perfect tential reasons for contraceptive failure analyzed. The second important param- conditions. The perfect use preg- were associated with eter to be considered for new drug devel- nancy rate of combined oral con- – irregular OC intake in 230 (42.2%) opment of oral contraceptives is bleed- traceptive users (COC) is 0.3% per – vomiting and/or diarrhea in 100 ing control. This aspect is discussed in year [663]. (18.3%) the second part, followed by the descrip- ● User effectiveness or typical effec- – use of antibiotics in 85 cases (15.6%). tion of the non–contraceptive benefits tiveness: the Pearl index number In 99 cases of contraceptive failure and mild to severe adverse events. for use that is not consistent or al- (18.2%), the analysis suggested perfect ways correct. The typical use preg- OC use. The reasons for the unplanned 2.1. Contraceptive Efficacy nancy rate among COC users var- pregnancies in 31 women (5.7%) could The effectiveness of contraception can ies depending on the population not be analyzed because of missing in- be typically expressed by two methods: being studied, ranging from 2– formation. – Time table analysis: calculation of a 8.6% per year [30, 196, 235, 663], separate contraceptive effectiveness see also summary table [220]. Methods for evaluation of contracep- rate for each month of the study, as – The Pearl Index calculation for stud- tive efficacy well as for a standard period of time ies in Europe compared to the US of- – Inhibition of ovulation: The contra- (usually 12 months). Use of life table ten shows higher values for studies ceptive of an oral hormonal methods eliminates time-related bi- performed in North America. This contraceptive can also be evaluated ases (i.e. the most fertile couples get- was recently shown again by Dinger by observing follicular growth, ovu- ting pregnant and dropping out of the et al. (2011) 151], probably due to lation and corpus luteum formation study early, and couples becoming higher rates of obesity, inadequate in- via assays performed on ve- more skilled at using the method as take and low adherence to the medical nous blood samples or serial ultra- time goes on), and in this way is supe- regimens. sound examinations. These tests are rior to the Pearl Index [521]. Further- done to evaluate the inhibitory po- more at the same time information Parameters affecting contraceptive tency (ovulation inhibition dosage) of about adverse reactions and drop-outs efficacy new progestins. due to adverse reactions can be listed Contraceptive efficacy may be impaired The ovulation inhibition dose given in by time of use. by [622]: mg or µg per day reflects the mini- – Pearl Index: The Pearl Index intro- – User’s negligence/missing pills: ir- mum dosage of a steroid necessary duced by Raymond Pearl (1933) regular use or missing more than one for ovulation inhibition and ranges [505] is often used to compare the ef- active pill in a packet is the most com- from 0.03 mg for to 4 mg fectiveness of various methods of mon cause of contraceptive failure: for norethindrone. contraception.. It is expressed as the 30% (age 18–30) [557], 48–84% “number of unintended pregnancies (50% during the first 3 cycles) (age Follicular Growth as Parameter of in 100 normally fertile women over 13–19) [170, 557], 74% (age < 14), Contraceptive Efficacy the period of one year”. an average of 3 pills per cycle (ado- – A review by Milsom and Korver To calculate a Pearl Index for a par- lescents) [35], 33% failed to take pills (2008) [462] analyzed the incidence ticular study the total number of regularly during the first 3 cycles, of ovulation with available COCs, tra- months or cycles of exposure for wo- adolescents forgot to take on the aver- ditional progestin-only-pills (POPs)

60 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

and with a POP (75 µg tive methods (i.e. condoms, if a sexually 3) a second-generation to a first-genera- desogestrel). transmitted infection [STI] protection in tion, or – The quality and results of many trials the relationship is not necessary). Using 4) various products containing a certain have been impaired by inadequate as a competitor OC a market leader as progestin. ovulation criteria, i.e. the progester- “gold standard”, these trials are re- The minimum duration of the trials one levels defining ovulation have quired for approval of a new OC. was six cycles. Trials involving mo- differed among the various studies. nophasic and multiphasic products Based on serum progesterone – Large clinical surveillance studies were analyzed separately. threshold for exclusion of ovulation: – Low dose EE pills with modern Twenty-two trials have been included Spona et al. (1997) [625]: > 5 nmol/l; progestins and formulations: Con- in this review. The data from one trial, Elomaa et al. (1998) [168]: traceptive failure in association with comparing pills containing levonor- > 9.6 nmol/l; oral contraceptive pills has been re- gestrel (LNG) to those containing ge- Kuhl et al. (1985) [389] > 9.6 nmol/l. cently reported by Dinger et al. (2011) stodene (GSD), showed that gesto- Birtch et al. (2006)[53] observed [151] analysing outcome data from dene may be associated with less in- ovulation using ultrasound evidence 52,218 U.S. participants in the Interna- termenstrual bleeding but both prod- of corpus luteum formation as the tional Active Surveillance Study of ucts showed similar patterns of spot- ovulatory criterion, but the associated Women Taking Oral Contraceptives – ting, breakthrough bleeding and the hormone levels were extremely low a large, prospective, controlled, non- absence of withdrawal bleeds. Results (progesterone 2.5 nmol/l). The re- interventional, long-term cohort study are given in the section on contracep- maining studies used a variety of other with active surveillance of the study tive efficacy. criteria to assess ovulation. In the larg- participants. Low rates of loss to fol- Contraceptive efficacy tables: see est study n = 209) [641], ultrasound low-up have been ensured by a com- summary of this section. measurements were scheduled during prehensive follow-up procedure. Con- days 18–21 of the cycle, which is con- traceptive failure rates are described Contraceptive efficacy sidered the least critical period with by the Pearl Index and the life-table – EE dosage: In a Cochrane review by respect to escape ovulation. Despite analysis. Inferential statistics for con- Gallo et al. (2011) [200] pregnancy substantial follicular growth (maxi- traceptive failure are based on Cox re- rates seemed to be the same between mum follicular diameter > 10 mm in gression models. Results are given in the group receiving OC containing > 10% of the cycles), no ruptured fol- the section on contraceptive efficacy. ≤ 20 µg EE compared to those women licles were observed and an absence – Modern regimens of COC: Dinger et receiving a combined OC containing of escape ovulation was therefore al. (2011) [151] Analyses are based on >20 µg EE, but the studies may not claimed. 1,634 unintended pregnancies during have been large enough to have statis- – Ovulation rates were found to be 2% 73,269 woman-years of oral contra- tical significance. for COCs containing 30 µg to 35 µg ceptive pills exposure. Contraceptive In a large prospective observational EE and 1.1% for COCs containing failure rates adjusted for age, parity study with modern COC a clinically 15 µg to 20 µg of EE [462]. and educational level showed a slight relevant difference in the rate of con- – In a Cochrane Library systematic re- increase with higher body mass index. traceptive failure was not observed view of COCs that compared COCs with respect to OC preparations that with EE ≤ 20 µg to higher dose COCs Cochrane reviews contain an dose of with EE > 20 µg, the authors found – In 2011 Gallo et al. [200] updated a < 30 or ≥ 30 µg; both doses were as- that the effectivness of the regimens – systematic Cochrane review of trials sociated with high effectiveness assessed by monitoring ovulation in- [201] comparing a combination OC [151]. hibition – was comparable [199]. product containing ≤ 20 µg EE with a – Progestin dosage: all COC contain a – Various regimens: the divergent another containing > 20 µg EE in progestin in a dosage above the ovu- methodology for ovulation detection terms of contraceptive effectiveness, lation inhibition dose; to date only in these studies make a comparison of bleeding patterns, discontinuation, one EE-free contraceptive, which various dose regimens difficult, but and side effects. The high dropout also inhibits ovulation, is on the mar- all regimens showed high levels of ef- rates in many trials make the results ket, i.e. desogestrel (75 µg/day). fectiveness [70]. hard to interpret. Results are given in – Type of progestin: the section on contraceptive efficacy. ● Third generation progestins: In a Number of unintended pregnancies as – Maitra et al. (2004) [436] and (2007) Cochrane review by Maitra et al. a parameter of contraceptive efficacy [437] assessed randomized trials (2004) [436] and (2007) [437] re- Background: Contraceptive efficacy evaluating combined OCs with garding contraceptive effective- can be measured based on the number < 50 µg EE comparing ness, pills containing gestodene of unintended pregnancies during OC 1) a third-generation progestin (deso- (GSD) were also found to be com- treatment in a trial exposing a definite gestrel, , gestodene) to a parable to those containing deso- number of women in the reproductive second-generation (, gestrel (DSG) in the standard age (mostly 18–40 years) (with or with- ), 30 µg estrogen dosage. However, out proven fertility based on previous 2) a third-generation progestin to a first- more pregnancies occurred when pregnancies) to a new contraceptive generation (norethindrone, ethy- pills containing 20 µg EE were method without using other contracep- nodiol), used. In contrast to pills containing

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 61 Oral Contraceptive Pills

DSG, those with GSD render bet- dy year, and 4.7% and 6.7%, respec- tinued using OCs in the EURAS-OC ter cycle control, although the con- tively, after the third year. The ad- study with the intention of becoming tinuation rate was higher in women justed hazard ratio was 0.7 (95% CI: pregnant [129]. using DSG pills. 0.6–0.8). Direct comparisons of the ● : In the analysis by 24-day and 21-day regimens of – Body mass Maitra et al. (2007) [437] the drospirenone and norethisterone, The impact of the BMI on the contra- characteristics of pills containing respectively, also showed lower con- ceptive efficacy is analyzed in a re- drospirenone (DRSP) were found traceptive failure rates for 24-day view by Burkman et al. (2009) [69] to be similar to those with DSG regimens. Obesity seems to be associ- as follows: with regard to pregnancy preven- ated with a slight reduction of contra- – Negative effect: Some studies have tion, cycle control and side effects. ceptive effectiveness. suggested that a high body weight or ● Drospirenone-, levonorgestrel-, – Age: The contraceptive failure by age body mass index (BMI) may have a desogestrel-, and -con- follows a biphasic pattern, which is in negative impact on the efficacy of taining pills: A large study by line with findings that female fecun- hormonal contraceptive methods Dinger et al. (2011) [151] showed dity peaks between age 20 and 30 [218, 219, 260, 262, 738]. that there was little variation in the years [223, 408, 722]. – Negative trend: Other studies have contraceptive effectiveness among A lower rate of contraceptive failure demonstrated a non-statistically sig- various weight and BMI cate- was found in women who were ≥ 30 nificant trend toward reduced contra- gories. years old and in women who had used ceptive efficacy (after adjustment for ● acetate: In con- OCs for a longer duration of time. demographic characteristics) [65, 66, trast, there was a significant corre- The decrease in contraceptive failure 67]. lation between body composition rates with increasing age likely re- – No association: Others have sug- and contraceptive effectiveness for flects the decline in the overall rate of gested that there is no association be- OCs that contained chlormadinone fecundity with advancing age. In- tween BMI and risk of unintended acetate (CMA), which is a proges- deed, lower rates of planned preg- pregnancy [362, 691]. tin that is not marketed in the nancy were observed in older women The EURAS-study shows little or no ; increased BMI who stopped OC use during the impact of body composition on con- (≥ 30 kg/m2) and weight (≥ 75 kg) EURAS-OC study with the specific traceptive effectiveness of COC (ex- were associated with a higher rate intention of becoming pregnant ception: con- of failure [151]. The reduced con- [130]. taing COC – see above) in a compli- traceptive effectiveness of CMA– – Duration of use: The reduced failure ant “typical use” population in Eu- containing OCs in heavier women rate observed in the EURAS-study rope, the same may not be true in may reflect the fact that CMA is with an increasing duration of use other populations, such as in the highly lipophilic and has been may be related to the fact that those United States, where the rate of obes- shown to accumulate in adipose women who are most likely to experi- ity is high [151]. According to Dinger tissue [198]. In overweight and ence contraceptive failure do so early, et al. (2011) 151], it is not possible, obese women, in whom adipose which results in a group of women however, to assess whether the low tissue mass is increased, this could that is increasingly dominated by the failure rates reported in the EURAS- result in an altered fat distribution most conscientious users and/or the study for overweight and obese and potentially lead to (temporar- least fertile users [151]. women would also be seen in popu- ily) subtherapeutic levels of sys- – Parity: Parous women were more lations associated with a substantial temic hormone. likely to experience a pregnancy dur- amount of incorrect OC use or in po- ● acetate (CPA): an ing OC use than nulliparous women. pulations with a higher proportion of increase in contraceptive failure This outcome was not unexpected; women defined by the World Health rate similiar to CMA is expected parity is associated with many fac- Organization to be class II or III obese for 2mg (CPA) tors, which include established fecun- (BMI ≥ 35 kg/m2). It is probable that containing OCs, due to similar li- dity in the past [662]. While parous most OCs are dosed adequately for pophilic affinity of CPA [533]. women have “proved” their fertility, OC users who are overweight or who nulliparous women have not; thus, belong to the category classified – Modern regimens of COC: 21+7 among any group of nulliparous by the World Health Organization versus 24+4 women will be some women who are as class I obesity (BMI, ≥ 30.0– An analysis by Dinger et al. (2011) infertile (or have partners who are in- 34.9 kg/m2); however, it is conceiv- [151] based on 1,634 unintended fertile) whose inclusion in the group able that many OCs are not dosed ad- pregnancies during 73,269 woman- will reduce the overall rate of fertility equately for OC users who are classi- years of oral contraceptive pills expo- [265]. This was illustrated by Howe fied as being class II or III obese. sure, revealed life-table estimates of et al. (1985) [265], who showed that – With the increasing use of low-dose contraceptive failure for a 24-day re- parity was associated strongly with OCs among women of different body gimen of drospirenone and ethinyl fecundity. The finding that fertility is weights or BMIs, evaluation of their estradiol and 21-day regimens of higher in parous women, compared contraceptive efficacy for women of other of 2.1% and with nulliparous women, was also ob- higher body weight or BMI is impor- 3.5%, respectively, after the first stu- served in those women who discon- tant [69].

62 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

Summary tables for contraceptive ef- Efficacy based on ovulation inhibition use, missed pill management, and ficacy of COC: The contraceptive effi- studies drug interactions. cacy is listed in the US patient informa- – The overall incidence of ovulation Age of users: A lower rate of contra- tion leaflet in a table created by Hatcher according to a literature search by ceptive failure was found in women (2004) [234] and Trussell and Kowal Milsom and Korver (2008) [462]: who were ≥ 30 years old [151]. (2004) [660] and is also published by the ● COCs containing 30–35 µg EE: Duration of use: A lower rate of con- IHS National Pharmacy & Therapeu- 2.0% (95% CI: 1.1–3.3) traceptive failure was found in tics Committee Review: ● COCs containing 15–20 µg EE: women with a longer duration of OC Oral Contraceptives (2010) [339] 1.1% (95% CI: 0.60–2.0) use [151]. (Tab. 1). ● Phasic COCs: 4.6% (95% CI: Parity: Parous women were more 2.8–6.9) likely to experience a pregnancy dur- Summary ● Desogestrel–only pill (75 µg/ ing OC use than nulliparous women Methods of evaluation of contracep- day): 1.25% (95% CI: 0.03–6.8) [151]. tive efficacy: ● Traditional POPs: 42.6% (95% Ethinylestradiol dosage: even – Life-table analysis: calculates a CI: 33.4–52.2) for low dose formulations (< 30 or separate contraceptive effectiveness ● The findings indicate that COCs ≥ 30 µg) a high effectiveness was rate for each month of the study, as and the desogestrel POP are found [151]. well as for a standard period of time equally effective in suppressing Progestins: only chlormadinone ac- (usually 12 months). Use of life table ovulation, whilst the traditional etate COCs show a lower contra- methods eliminates time–related bi- POP formulations are less effec- ceptive efficacy in women with in- ases. tive. creased BMI (≥ 30 kg/m2) and weight – Pearl Index analysis: the number of (≥ 75 kg) [101]. unintended pregnancies per 100 Efficacy based on contraceptive fail- – Final statement: Overall, COCs in women per year; often used to quan- ures as clinical endpoints dosages available worldwide are tify effectiveness. – The perfect use pregnancy rate of among the most effective contracep- ● method effectiveness: pregnancy COCs is 0.3% per year [663] and the tive methods when used consistently rate assuming perfect use of the typical use pregnancy rate varies de- and correctly [661]. method pending on the population being stud- A summary of contraceptive efficacy is ● user effectiveness or typical effec- ied, ranging from 2–8,6% per year given in Table 1. tiveness: pregnancy rate consider- [663] (See summary table published ing inconsistent or negligent use of by Guttmacher Institute (2010) 2.2. Menstrual Bleeding Pat- the method. [220]. tern – Normal and Pathological – The Pearl Index in COC studies done The tissue damage and subsequent re- Parameters affecting contraceptive in Europe is lower than data obtained pair occurring during are efficacy from US studies. the result of a complex interplay be- Contraceptive efficacy may be impaired – The method failure rate for COC is tween the endocrine system and the lo- by (Speroff & Darney, 2005) [622]: low, but the failure rate due to patient cal immune system [124, 125, 126, – User’s negligence: missing more negligence is higher and influenced 346]. than one active pill in a packet or ir- i.e. by irregular intake, missing pills, regular use is the most important drug interactions, insufficient patient Progesterone is seen as a critical steroid cause of contraceptive failure: delay instruction, concomitant medical for endometrial differentiation. Men- in starting the next packet of active treatment (pharmacy or over the struation occurs in two phases: in the pills (i.e., extending the pill-free, in- counter including herbal medi- first phase a decrease in the progesterone active or placebo pill period beyond 7 cine), vomiting and diarrhea. level leads to vasoconstriction of the days), – Contraceptive failure rates were arterioles, caused by local cytokines. – Intestinal malabsorption of active found to decrease substantially from This phase lasts about 36 hours and is pills due to vomiting or diarrhea, 30 years of age and as the duration of thought to be reversible. The second – Drug interactions with active pills OC use increased. phase of menstruation, however, which that decrease contraceptive estrogen – OCs were associated with a high level involves the activation of lytic mecha- or progestogen levels of contraceptive effectiveness in a nisms, is irreversible. This phase is inde- – Body mass index and absolute “typical use” setting (ie, outside of a pendent of progesterone [369]. This weight had little, if any, influence on setting) in Europe. means, however, that only within the the contraceptive effectiveness of first 36 hours after the progesterone drop OCs that contained drospirenone, die- Contraceptive efficacy of COC is de- an add-back therapy with progesterone nogest, desogestrel, and levonorge- pendent on can usually be successful [604]. strel, but the contraceptive efficacy of Socio-economic-status: Based on lipophilic progestins such as chlor- education and social economic sta- Prominent among factors leading to dis- madinone acetate (may be also true tus the efficacy of COCs may be continuation of oral contraceptives is the for cyproterone acetate) is impared by lower for those in the lowest quar- occurrence of side effects, including in- increased BMI ≥ 30 kg/m2) and tiles due to the poor information sta- termenstrual bleeding, , weight weight ≥ 75 kg). tus of the patient with regard to COC gain, and [3, 618].

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2.2.1. Definition of irregular bleeding Table 1. Contraceptive efficacy of various contraceptives (Pearl Index). Mod. from Trussel 2007, http://www.arhp.org/uploadDocs/YD_Summary_Efficacy.pdf – For the purpose of performing studies the World Health Organization has % of women experiencing % of women classified unplanned bleeding into 2 an unintended pregnancy continuing within the first year of use use of 1 year categories [46]: Breakthrough bleed- ing, which requires sanitary protec- Method Typical use Perfect use tion, and spotting, which does not re- Chance 85* 85* – quire sanitary protection. Spermicides 29* 18* 42* – Because of the lack of uniformity in Coitus interruptus 27* 4* 43 Fertility observation 25* – 51* studies of cycle control, the World Standard-day-method – 5* – Health Organization has issued rec- Two-day-method – 4* – Ovulation method – 3* – ommendations aimed at standardiz- Sponge – – ing the collection and analysis of Parous 32* 20* 46* data, including definitions of “bleed- Nulliparous 16* 9* 57* Diaphragm 16* 6* 57* ing” (requires sanitary protection) Condom and “spotting” (does not require pro- Female condom (Femidom®) 21* 5* 49* Male condom 15* 2* 53* tection) and a “bleeding/spotting” Oral hormonal contraceptives episode (one or more days with bleed- Combined oral hormonal contraceptives ing or spotting bordered by days Estrogen-free ovulation inhibitor Cerazette 0.4 (0.09–1.2) 0.14 n. a. without bleeding or spotting). (SPC) The WHO furthermore advises that OC with estradiol derivatives outcomes should be measured using a : Qlaira® 18–50 years: 18–50 years: n. a. 0.42 (max 95% CI 0.77) 0.79 (max. 95% CI reference period of at least 84–90 days (SPC) (1.23) to identify changes over time while (SPC) 18–35 years: 18–35 years: n. a. still fairly assessing bleeding patterns, 0.51 (max 95% CI 0.97) 1.01 (max. 95% CI and the terms used to assess bleeding (SPC) 1.59) during the pill-free period should be Combined Evra® 0.90 (0.44–1.35) 0.72 (0.31–1.13) 68* defined using at least five bleeding (SPC) (SPC) outcomes, namely, the proportion of Combined NuvaRing® 0.96 (0.64–1.39) 6.64 (0.35–1.07) 68* women with prolonged, frequent, in- (SPC) (SPC) frequent, or irregular bleeding/spot- Progestin-only pill Levonorgestrel (30 µg/Tab) ting episodes and those with amenor- Microlut® 4.14 (SPC) n. a. rhea during the reference period [46]. Depoprogestins (injectables) – The various studies are difficult to acetate 56* DMPA (150 mg) compare because, despite this formal Depoclinovir® 0.3 (SPC) classification, clinical trials have va- DMPA (104 mg) Sayana® 0 (SPC) ried in their terminology and methods Noretisteron enantate of recording menstrual irregularities. Noristerat 200 mg® 0–2.3 (SPC) Postcoital pill – In addition, there is wide variation Levonorgestrel (PiDaNa®) n. a. (SPC) among women as to their individual Day1: 2.5% per cycle Day 1–3: 1.7% per cycle tolerance to bleeding abnormalities, Day 4–5: 2.8% per cycle their perceptions of heavy vs light Ulipristal (EllaOne®) n. a. (SPC) Day 1: 0.9% per cycle bleeding, as well as their need for pro- Day 1–3: 0.9% per cycle tection [658]. Day 4–5: 0% per cycle Intrauterine devices Nova T 380® 0.6 (SPC) Further definitions: Multiload-Cu 375® 0–1.8 (SPC) ParaGard™ (***) 0.8* 0.6* 78* – Intermenstrual bleeding: all bleed- Intrauterine systems ings that occur between the normal Mirena® 0.2* 0.2* 80* withdrawal bleeding periods at the 1. year 0.2%; 5. year 0.7% (SPC) end of the hormonal treatment period. Contraceptive subdermal Unexpected bleeding is a major prob- implants Ketodesogestrel lem for women. Implanon 0.05 0.05 84* – Prolonged bleeding: pre- or post- Norgestrel Jadelle menstrual bleeding. (previous: Norplant 2)(***) 0.08–0.17 (Rx_List, USA) – Severity of bleeding: breakthrough Female sterilisation**) 0.5* 0.5* 100* bleeding normally requires sanitary Male sterilisation 0.15* 0.1* 100* protection, whereas spottings do not. SPC = summary of product characteristics; n. a.= not available; CI = confidence interval. – Absence of withdrawal bleeding *according to Trussel 2007; ** depending on operation technique, skill of doctor performing the operation, age, time intervall after operation, *** not available on german market (“pill amenorrhea”): no menstrual bleeding during the pill free interval.

64 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

– Dysmenorrhea: pain in relation to Incidence, dosages and regimen: see gestrel and 20 µg EE, while a lower menstruation. also summary rate was observed in those receiving Mears & Grant (1962) [457] sum- 30 µg EE (3,0% after 6 cycles and Etiology of breakthrough bleedings: marized the results with the higher 1,4% after 12 cycles, respectively) [8]. – Skipping a pill is a common cause of dose formulations used in previous breakthrough bleeding [559]. years: Treatment – Inconsistent use, such as failure to – Norethisterone: Tyler et al. (1961) Preconditions: take the pill at the same time every [665] using 10 mg of norethisterone, – Exclusion of an unintended pregnancy day, or lack of adherence to the pill– reported amenorrhea in 6% of the is the first step of clinical workup. taking instructions, often triggers cycles; Pincus et al. (1959) [519], in – Treatment of missing withdrawal breakthrough bleeding [560]. trials in Humacao, Puerto Rico, and bleedings has no medical but in most – Taking some prescription and over- Haiti, reported 2.2% cases, rather a psychological indica- the-counter , as well as – Norethynodrel: Trials in the UK tion – to counsel and advise those herbal supplements, may interfere showed the amenorrhea rate to vary fearing a pregnancy or possible infer- with the activity of OCs to alter bleed- from 1 to 9% [163, 457]. tility, or depending on the ethnic and ing patterns and contraceptive effi- – Estrogen/progestin-balance: The cultural background of the individual, cacy [698]. lowest incidence of amenorrhea with expressing concern for their health in – Smoking is associated with such anti- norethynodrel (2,5 mg) was found in general. estrogenic effects as early meno- combination with the highest estro- Informed consent: Women should be pause, , and menstrual gen content (150 µg of mestranol). informed that: abnormalities [41]. When norethynodrel was used it ap- ● post-pill fertility is not impaired by peared that in amenorrhoeic cycles missing regular withdrawal bleed- 2.2.2. Pill Amenorrhea (silent menstrua- women often had some spotting dur- ings and do not lead to health risks. tions) ing tablet–taking and none during the In the case of regular intake no in- All women using OCs can experience gap, whereas the women on norethis- tervention is necessary. some cycles without a withdrawal bleed- terone acetate had the spotting during ● By changing dosages and regi- ing. The occurrence of such a menstrual the gap without periods, which was mens intermenstrual bleedings may abnormality, however, may increase the therefore regarded as a menstrual occur instead of a lack of with- fear of an unwanted pregnancy in some flow [457]. drawal bleedings. individuals, especially those who have – EE ≤ 20 µg versus EE > 20 µg: In a Treatment options: not adhered to the pill-taking instruc- Cochrane Library review, 13 combi- – Patient information (see above) tions. nations of COCs with regard to their – A low dose of EE (i.e. 10 µg/day) may Amenorrhea and women’s perception: EE dosage were analyzed by Gallo et be added to the regimen or the patient – Lack of withdrawal bleeding leads to al. [200]. No differences were found may be switched to a pill with a a latent fear of pregnancy, especially in contraceptive effectiveness. Com- higher dose of estrogen. in women taking OCs irregularly. pared to the higher-estrogen pills, – If higher EE dose pills fail to increase – According to the ethnic origin and re- several COCs containing 20 µg EE re- the thickness of the suf- ligious/cultural background of the sulted in higher rates of early trial dis- ficiently, the dose of progestin can be women regular monthly bleedings are continuation (overall and due to ad- decreased, a sign of good health. verse events such as irregular bleed- – Changes in the estrogen/progestin bal- – Some women appreciate the occur- ing) as well as increased risk of bleed- ance as well as the regimen (i.e. bipha- rence of amenorrhea while using a ing disturbances (both amenorrhea or sic or triphasic regimen) can be tried. COC. infrequent bleeding and irregular, Incidence (total): The incidence of a prolonged, frequent bleeding, or Summary pill amenorrhea (“silent menstrua- breakthrough bleeding or spotting) In Incidence (total): The incidence of a tions”) in users of COCs varies ac- other words, comparing pills with pill amenorrhea (“silent menstrua- cording to the regimens and the type 20 µg EE and 150 µg desogestrel with tions”) varies from 5–20% in users of and dosage of progestins and estro- those containing 30 µg EE and COCs according to the type and dos- gens, ranging between 5–20% (i.e. 150 µg desogestrel showed an odds age of progestins, estrogens and the combined OC with 30 µg EE versus ratio (OR) of 1.49 (0.75–2.97) after regimen followed. 4-phasic with dienogest and estradiol cycle 3 and an OR of 1.43 (0.65–3.12) Incidence relative to time of use: The valerate) [5]. The rate is higher using after cycle 6 thus demonstrating a incidence of absent withdrawal bleed- progestins with longer half-lives and higher tendency for amenorrhea in ing is highest following the first cy- low EE-dose formulations. the 20 µg EE dose formulation. cles and declines with use from 10% Incidence relative to the time of use: A – Incidence of no withdrawal bleed- to 5% of cycles in a study with a 20 µg 20 µg dose of EE in combination with ings: EE 20 µg versus EE 30 µg: In a EE/100 µg levonorgestrel pill per- low dose levonorgestrel (100 µg) comparison trial withdrawal bleed- formed by Ahrendt et al. (2009) [5]. caused no withdrawal bleeding after ings of 4.2% after 6 cycles and 3.0% In another study 4,2% and 3,0% of a the first cycle in 10% of those studied after 12 cycles were reported for a group receiving a preparation con- and in 5% during the subsequent 7 group receiving a combination OC taining 150 µg desogestrel and 20 µg cycles [5]. preparation containing 150 µg deso- EE experienced no withdrawal bleed-

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ings after 6 cycles and 12 cycles, re- Causal relationship to OC-formula- within 6 months after starting a new spectively. In comparison, for those tion: No relationship between the regi- prescription because of side effects receiving a 30 µg OC with the same mens and the type and dosages of [561]. Irregular bleeding was the most progestin, absence of withdrawal bleed- estrogens and progestins has been ob- common cause (12%), followed by nau- ings were reported in 3.0% after 6 cy- served in view of the incidence of a post sea, , and mood changes, cles and 1.4% after 12 cycles [8]. pill amenorrhea. which ranged from 5% to 7%. A survey Ethinyl estradiol dosage: Lowering the of over 6,500 women who were either dosage of EE from 50 to 30 or 20 µg Irregular cycles at pretreatment: In a current or former users of oral contra- per day leads to a higher rate of literature review Hammerstein (1977) ceptives showed that women experienc- amenorrhea: [224] analyzed various studies with post ing bleeding irregularities during the – EE ≤ 20 µg vs EE > 20 µg: In a pill amenorrhea in women using older first 3 months of use were almost twice Cochrane review by Gallo et al. higher dose preparations. In 10–57% of as likely to discontinue the pill within 2 (2011) [200] OCs with EE ≤ 20 µg the cases the post pill amenorrhea was years of use when compared with and EE > 20 µg were compared. Sev- due to a pregnancy. In 35–71% of all women who did not experience bleed- eral COCs containing 20 µg EE re- cases cycle irregularities prior to OC ing (p < 0.001) [560]. sulted in higher rates of early trial dis- use, and in 3–43% in combination with continuation due to overall adverse galactorrhea had been reported. Understandable concerns about poten- events such as irregular bleeding, or tial side effects of oral contraceptives, out of concern for the increased risk The incidence of pre-existing oligo- embarrassment about unexpected side of bleeding disturbances (both menorrhea varies in different studies of effects and insufficient bleeding control, amenorrhea or infrequent bleeding post-pill amenorrhea, but about half the and annoyance lead these women to and irregular, prolonged, frequent women who present with post-pill ame- abandon OCs [524, 561]. bleeding, or breakthrough bleeding or norrhea show some irregularities in spotting). menstruation before starting the treat- Most women do not know that the inci- – Estrogen-free OCs: In users of the ment [165]. dence of breakthrough bleeding is gen- EE-free oral contraceptive with de- erally greatest in the first 3 to 4 months sogestrel (75 µg/day) a pill amenor- Clinical workup: As a conclusion, in after starting OCs [658] and steadily de- rhea was found in 5–20 % of the cy- cases with preexisting disturbances of clines until it stabilizes by the end of the cles [111]. the menstrual cycle the higher risk for a fourth cycle [619]. At the time of first Progestins: Using progestins with a post pill amenorrhea due to endocrine prescription women must be informed longer half-life leads to higher rates disturbances (i.e. hyperprolactinemia about the higher rate of bleeding distur- of pill amenorrhea ( versus and hypothyroidism; hyperandroge- bances during the first three cycles as ) due to a slower decline of nism) should be evaluated at least after this could enable many of these women serum levels in the pill free interval. 3–6 months by endocrine testing (i.e. to cope with the bleeding and stick with Regimen: The importance of the regi- , TSH, fT3, estradiol, FSH, LH an effective contraceptive method. In ad- men with respect to pill amenorrhea is and and DHEAS if indi- dition, new OC users should be informed pointed out by the following: cated by signs of hyperandrogenism). about non-contraceptive benefits of – Using a prolonged regimen, i.e. 24+4 OCs: improved menstrual regularity and with drospirenone, leads to a higher 2.2.3. Intermenstrual bleedings [428] decreased menstrual blood loss, dys- incidence of amenorrhea (5–10%) Prevalence: The intermenstrual bleed- menorrhea, and risk of ovarian and en- with higher rates at the beginning and ing that occurs in approximately 10% to dometrial cancer. lower rates by time of OC use [5]. 30% of women in the first month of oral – In users of the 26+2 regimen (four– contraceptive use is best managed by en- Women who discontinue OCs on their phasic pill) with dienogest and couraging users to continue the regimen own switch to less effective methods of estradiol valerate a high rate of pill and reassuring them that the problem birth control or use no method [524, amenorrhea is observed in 15–20% of usually disappears within a few cycles 561]. The consequences thereof may be all cases [5]. [658]. unexpected pregnancies and increased abortion rates [559]. It would be advis- Post Pill Amenorrhea Consequence of intermenstrual bleed- able to periodically ask those users Definition: A post pill amenorrhea is per ings = discontinuation: About 20% of whether they are satisfied with OC use. definition the absence of bleedings for at women surveyed in a nationally repre- least 6 months following the discontinu- sentative sample had discontinued oral Factors contributing to breakthrough ation of the pill [165]; various defini- contraceptives (OCs) on their own or at bleeding: Breakthrough bleeding may tions are used in the literature (i.e. 3 the recommendation of their physician be due to any the following factors: months) and for most women 6 months due to bleeding or spotting [428, 524]. physiological effects of OCs on the en- seems to be too long. Menstrual abnormalities are consist- dometrium, OC-related parameters, in- ently cited as a common reason for dis- cluding dose, formulation, and regimen, Incidence: According to the 6 month continuing OCs [191, 560]. A prospec- patient behavior, including compliance, definition of amenorrhea a post-pill tive US study of 1657 women per- using concomitant medications, ciga- amenorrhea occurs in 2–3 % of all OC formed in the 1990s reported that 37% rette smoking and benign or malignant users [165]. of OC users had stopped taking OCs pathology of the uterus.

66 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

Estrogen and progestin effect on the and may not provide the same non– Progesterone derivatives: endometrium: contraceptive benefits as higher estro- – Pregnanes include progestins as – Progestin and estrogen in combina- gen products, such as reduction in risk chlormadinone acetate*, cyproterone tion OCs have profound effects on the of , protection against acetate*, medroxyprogesterone ac- endometrium, which, though not con- functional ovarian cysts, and improve- etate (used i.e. for injectable contra- tributing to contraception, do lead to a ments in acne [201]. ceptives) (* not available in the US) predictable pattern of bleeding or 19-norpregnane derivatives developed such problems as breakthrough bleed- Progestin type, content & cycle con- in , are also derived from pro- ing or lack of withdrawal bleeding. trol (IHS 2010) [339]: gesterone without an angular 19-me- – Estrogens: normally, estrogen causes Progestin content may also affect cycle thyl group like norethindrone. They the endometrium to proliferate. Pro- control, because even moderately low include , NOMAC, and gesterone stabilizes the growing uter- doses of either EE or progestin can in- demegeston and . The ine lining. crease the incidence of breakthrough norpregnane derivatives have similar bleeding. properties to 17α-hydroxyprogeste- Estrogen dosage (IHS 2010) [339]: – Progestin dosage: When 3 COCs rone derivatives, but, in contrast to, – Since the introduction of OCs in with the same type of estrogen and for example, medroxyprogesterone 1960, the trend in formulation has progestin in different dosages (50 µg acetate has no androgenic, but rather been to use the least amount of hor- EE/100 µg norethindrone; 35 µg EE/ anti-androgenic properties. mone necessary to inhibit ovulation. 100 µg norethindrone; 35 µg EE/ NOMAC (NOMAC) has been re- Given that progestin is primarily re- 50 µg norethindrone) were compared cently approved for oral contracep- sponsible for the contraceptive effi- in 192 women over 8 cycles, the pill tion in combination with estradiol in cacy of OCs, the risk of pregnancy is containing the lowest amount of nore- 2011. not altered by decreasing the estrogen thindrone (35 µg EE/50 µg norethis- content. However, significantly low- terone) caused the highest rates of Each progestin differs in half-life, as ering the estrogen in OCs may ac- breakthrough bleeding, decreasing to well as in progestinic, estrogenic or anti- count for breakthrough bleeding. Un- 50% by cycle 8 as compared with estrogenic, androgenic or antiandro- planned bleeding, though, is not de- 35% for the group receiving the 35 µg genic, and partial antimineralocorticoid pendent solely on the estrogen com- EE/100 µg norethindrone pill and properties. Variations of the half-life, the ponent as variations in the progestin 25% in the 50 µg EE/100 µg norethin- progestinic and (anti)-estrogenic proper- dose can contribute to breakthrough drone pill group [572]. ties may explain the differing rates of bleeding as well [174]. – Type of progestin may affect break- breakthrough bleeding among formula- – As the estrogen content of OCs has through bleeding. tions [619]. declined, higher breakthrough bleed- All combination OCs contain either As shown by Endrikat et al. (2001) ing and spotting rates have been EE or mestranol and a variety of dif- [171] pills with the same quantity of EE noted, along with a possible decrease ferent substances derived either from but different progestins can have mark- in contraceptive efficacy [201, 200]. 19-nortestosterone or from progester- edly different effects on the break- Bleeding problems related to EE dos- one to make up the progestin compo- through bleeding rates. age: Gallo et al. (2011) [200] per- nent. The former progestins can be In a Cochrane review Maitra et al. formed a systematic review of trials further classified as gonanes or estra- (2005) [436] evaluated randomized tri- comparing a combined OC contain- nes [629]. als (n = 22) comparing combined OCs ing ≤ 20 µg EE with a combined OC 19-nortestosterone derivatives: with < 50 µg EE and various progestins containing > 20 µg EE in terms of – Estranes include norethindrone and over a minimum duration of six cycles. contraceptive effectiveness, bleeding its derivatives: norethindrone acetate, Trials involving monophasic and mul- patterns, discontinuation, and side ef- ethynodiol diacetate and , tiphasic products were analyzed sepa- fects. The high dropout rates in many which must be primarily converted to rately. of these trials, however, make the re- norethindrone to become biologically Gestodene (GSD) versus levonor- sults hard to interpret. active. gestrel (LNG): Based on data from one Compared to the pills containing the – Gonanes include levonorgestrel, nor- trial a COC with GSD compared to a higher doses of estrogen, several gestrel, desogestrel, gestodene, and LNG-COC caused less intermenstrual COCs containing 20 µg EE resulted in norgestimate. bleeding, but showed similar patterns higher rates of early trial discontinua- Dienogest (DNG) is the only with regard to spotting, breakthrough tion (overall and due to adverse nortestosterone derivative with a bleeding and the absence of withdrawal events such as irregular bleeding) as cyanomethyl group in position 17α bleeds [436]. well as increased risk of bleeding dis- instead of an ethinyl group. Unlike Gestodene (GSD) versus desogestrel turbances (both amenorrhea or infre- the other nortestosterone derivatives (DSG): COC with GSD when compared quent bleeding and irregular, pro- it has no androgenic, but even an anti– to DSG-COC led to better cycle control, longed, frequent bleeding, or break- androgenic effect, which corresponds although the continuation rate was through bleeding or spotting). to about 40% of that of cyproterone higher in women using DSG pills. Various factors: Low estrogen OCs may acetate. DNG has no Drospirenone (DRSP) versus deso- be more influenced by missed pills or or antimineralocorticoid properties gestrel (DSG): No differences have the concomitant intake of drugs [169], [394]. been found between COC with DRSP

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 67 Oral Contraceptive Pills and those with DSG with regard to preg- ● 20 µg EE: 20 µg EE/500 µg nore- estradiol in (E1). E1, how- nancy prevention, cycle control and side thisterone pills consistently had ever, does not show a proliferative effects. higher breakthrough bleeding rates effect on endometrium. Using a dy- Regarding acceptability, all the indices than the 20 µg EE/100 µg levonor- namic dose it was possible to adjust show that third (gestodene, desogestrel, gestrel pill. the rate of additional bleeding caused norgestimate) and second-generation In conclusion, a greater cycle control by the EE pills when using estradiol (LNG) progestins are preferred over may be achieved by titrating the EE valerate and dienogest in a 4-phasic first-generation pills containing nor- component of an OC in a balanced regimen. , norethindrone, ethynodiol ratio with the same progestin, but the – Comparing regimens. diacetate, lynestrenol or norethynodrel absolute quantity of EE in a given pill Available OC formulations, doses, [436]. may be less important than maintain- and regimens: More than 30 formu- ing a balance between the 2 hormones lations of combination OCs are avail- Duration of use or less important than the impact of able in the US, containing different Regardless of the progestin used or different progestins on breakthrough doses and types of estrogen and pro- the quantity of EE, breakthrough bleeding rates [428]. gestin [235]. OC regimens are avail- bleeding generally decreases with Pathophysiological background: able as biphasic, triphasic, extended– each successive cycle. One study that The balance between estrogen and cycle, and continuous use. compared 2 combination OCs com- progestins required for contracep- Biphasic and triphasic products & posed of EE/norgestimate and EE/ tion may also lead to progestin-in- cycle control [339]: norgestrel demonstrated reported duced and endome- ● It is not clear whether biphasic and bleeding rates of 11.3% and 10.6% trial atrophy, which can result in a- triphasic regimens offer any clini- during the first 6 cycles, that de- synchronous, irregular bleeding [174, cally meaningful advantage over creased to 5.1% and 6.3% in Cycles 254]. This has been primarily stud- monophasic OCs, although the 13 to 24, respectively [118]. ied in long-acting progestin-only overall reduction in progestin and/ contraceptives such as implants. Al- or estrogen exposure should be ac- Estrogen-progestin balance [428] terations in angiogenic factors [609] companied by a lower risk of – Most OC users worldwide take low- may play a role. Hysteroscopic stud- thromboembolic events. dose formulations, so designated be- ies have shown abnormalities in su- ● As reported by Mishell (1991) cause the estrogen component is perficial endometrial blood vessels [464] use of the older types of < 50 µg EE. This level of estrogen in in terms of size, proliferation, and biphasic (two levels of progestin) combination with a progestin pro- fragility in women using the levo- products declined relative to vides excellent contraceptive effi- norgestrel implant Norplant™ [253, triphasic products because of an cacy, but may be insufficient to sus- 254, 611]. indicated increase in breakthrough tain endometrial integrity in some Abnormalities in endothelial cells bleeding. women [365]. and extracellular matrix proteins ● In a Cochrane review last updated – Studies that have compared OCs con- [551], tissue factor [427], and en- in 2005, Van Vliet et al. [677] taining 20 µg EE with those contain- dometrial lymphoid cells [98] may compared biphasic with triphasic ing 30 µg or 35 µg EE have not been contribute to breakthrough bleeding OCs in terms of efficacy, cycle very useful for judging breakthrough in progestin-dominant environments. control, and discontinuation due bleeding rates because the products Furthermore, a direct effect of pro- to side effects. Only two trials met often also vary in the phasing and gestins and estrogens on endometrial inclusion criteria. One trial found type of progestin. expression and similar results with two biphasic – Some studies show more break- estrogen has been ob- OCs and one triphasic OC (all through bleeding with 20 µg EE pills served. The antiestrogenic effect of containing levonorgestrel/EE) [528, 8, 202], but others show equal progestins is based mainly on the sup- [407]. The other compared a or improved cycle control with the pression of estrogen receptors and ac- biphasic OC containing norethin- lower EE dose. tivation of involved in drone (Ortho 10/11™) with a – Endrikat et al. (2001) [171] con- estrogen metabolism such as 17-hy- triphasic OC containing levonor- ducted a study to compare different droxysteroid dehydrogenase and gestrel (Triphasil™) and another OCs with 20 or 30 µg EE: estrogen sulfotransferase, as well as containing norethindrone (Ortho ● 30 µg EE: Overall, the pill con- on the differentiation of the func- 7/7/7™) [508]. taining 30 µg EE preparation tionalis layer of the endometrium ● The biphasic product had inferior (30 µg EE/150 µg levonorgestrel) [394]. cycle control compared to the was used as a standard reference In the human endometrium, inacti- levonorgestrel triphasic product, preparation and showed a lower vation of 17β-estradiol to estrone is based on differences in cycles with cumulative incidence of break- catalyzed by 17β-hydroxysteroid intermenstrual bleeding (OR 1.7, through bleeding compared with dehydrogenase type 2 (17βHSD2) 95% CI: 1.3–2.2) and cycles with- the 20 µg EE/100 µg levonorgestrel [375]. Estradiol-based combined oral out withdrawal bleeding (OR 6.5, and 20 µg EE/500 µg norethiste- contraceptives cause bleeding prob- 95% CI: 3.1–13). rone pills over 13 cycles (1.0% vs. lems, because the 17βHSD2 (stimu- ■ On the other hand, the biphasic 4.1% vs. 11.7%, respectively). lated by progestins) rapidly converts product had comparable results

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to the triphasic product with the led to the development of the – Comparing regimens: same progestin. triphasic pill [464]. Phasic regimen: no Cochrane-based ■ After excluding poor-quality ● Though the multiphasic hypoth- differences among monophasic, bi- trials from the analysis, the au- esis is physiologically plausible, phasic and triphasic OCs have been thors concluded that cycle con- recent reviews of the literature reported with regard to better control trol might depend more on the have found that the evidence for its of the menstrual cycle. choice of progestin than the efficacy is too limited and meth- Extended-cycle: Using combined phasic regimen. odologically flawed to draw any pills as “off-label” or one of the three definitive conclusions about a de- FDA-approved 3 months pills will be Monophasic versus triphasic: crease in breakthrough bleeding of interest to those women who prefer Rosenberg et al. (1992) [558] evalu- [675, 676]. extended menstrual cycles ated 25 studies assessing cycle con- A continuous regimen: (Lybrel™) trol with various OCs. In general, Summary (90 µg levonorgestrel/20 µg EE) has products containing norgestrel and – Data base: Studies of cycle control only been approved in the US due to levonorgestrel (2nd generation prod- tend to have methodological prob- its association with high rates of ir- ucts) were found to cause a lower in- lems, including small sample size, lack regular bleeding. All extended cycle cidence of spotting and breakthrough of control for other factors that may af- regimens are in discussion for in- bleeding compared with norethin- fect the incidence of bleeding (i.e., creased steroid exposure per year be- drone acetate and norethindrone (1st chlamydial infection, cigarette smok- cause of missing pill-free intervals. generation), whether triphasic or mo- ing, age, missed pills, interacting nophasic. medications), differences in study de- 2.3. Non-contraceptive Benefits Two trials comparing two norethin- sign/analysis, and differences in defi- 2.3.1. Overview drone-containing triphasic products nitions of bleeding and spotting [21]. In the following section various non- vs a levonorgestrel-containing tripha- – Factors contributing to break- contraceptive benefits of combined oral sic product found that the levonor- through bleeding: physiological ef- contraceptives will be described and gestrel product was associated with a fects of OCs on the endometrium, analyzed with regard to dose reduction lower rate of intermenstrual bleeding OC-related parameters, including of estrogens and progestins and the use [159, 579]. dose, formulation, and regimen, of different regimens and new pro- women behavior, including compli- gestins. Initial data from the UK known Extended-cycle regimen: ance, using concomitant medications, as the Royal College of General Practi- 3-month pill: Women using extended- and smoking, and benign or malig- tioners Study (1974) [566] demon- cycle contraceptives i.e. the 3-month nant pathology. strated a significant reduction in menor- pill (30 µg EE/150 µg levonorgestrel) – Higher incidence during first three rhagia (50%), benign breast tumors have been found to experience more OC cycles: Cycle problems tend to (20%), dysmenorrhea (60%), iron defi- breakthrough bleeding than those us- lessen within a few months of OC ini- ciency anemia (40%), premenstrual syn- ing a standard 28-day pill, however tiation, regardless of formulation. drome (30%), acne vulgaris (20%) and the total number of planned and un- Strategies for dealing with cycle ovarian cysts (60%) for EE ≥ 50 µg/day. planned bleeding days may still de- problems include: informing the In reducing the dosage of estrogens and crease from 21 days of planned bleed- women that these problems tend to progestins, using new regimens (i.e. ing in a 28-day regimen to 7 days of decrease during the first 3 months of multiphasic pills) and developing new planned bleeding in a 3-month cycle use and that they should not discon- progestins to make products safer it must [15]. The number of bleeding days tinue or change the formulation dur- be proven at the same time that the new decreased with each cycle. ing this period; consideration of fac- products do not lose the non-contracep- Continuous 365-day regimen: An- tors that can contribute to problems, tive benefits as described for the pills other study examined continuous OC such as missed doses, chlamydial in- analyzed in the Royal College of Gen- use (20 µg EE/100 µg levonorgestrel) fections, smoking, and interacting eral Practitioners Study (1974) [566]. over a period of 1 year, and reported a medications; changes in regimen The following analysis of the non-con- decreasing number of bleeding days (adding estrogen or decreasing pro- traceptives benefits of combined oral over time [461]. In the case of con- gestin if bleeding occurs early in the hormonal contraceptives is based on a tinuous use, all bleeding was un- cycle, adding progestin if it occurs review of The ESHRE Capri Workshop scheduled, and any bleeding was con- late in the cycle, or doubling active Group (2005) [649]. sidered breakthrough bleeding. pills until the bleeding stops or for the Multiphasic OC regimens were de- rest of the cycles); or providing a 2.3.2 Non-contraceptive benefits in veloped with the intention of decreas- course of non-steroidal anti-inflam- relation to dosages, combinations and ing breakthrough bleeding by mim- matory drugs [21]. new steroids used for oral hormonal icking the rising and falling pattern of contraception estrogen and progesterone in the nor- – The type of progestin may affect 2.3.2.1. Dysmenorrhea (IHS 2010) mal menstrual cycle [670]. breakthrough bleeding. [339] ● After the introduction of the bi- – The estrogen-progestin balance is Definition: phasic pill, an increase in break- more important than the absolute – Dysmenorrhea is the occurrence of through bleeding was noted, which level of estrogen. painful cramps during menstruation.

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– It is defined as primary (associated prostaglandin release, thereby pre- nificant when reanalyzed using a with ovulatory cycles and with no or- venting abnormal uterine con- random effects model to compen- ganic pathology) or secondary (asso- tractility leading to reduced uterine sate for significant heterogeneity ciated with a condition such as en- blood flow and ischemic pain within the trials (OR 1.68, 95% CI dometriosis or ovarian cysts). [149]. 0.29–9.81). Prevalence: ● Several clinical trials have proven ● Not surprisingly, adverse effects – Dysmenorrhea is the commonest the efficacy of COC in treating were higher in the combined OC form of with a re- dysmenorrhea: group, although this outcome was ported prevalence of 50–90% among ● An open trial in 661 women (after reported by only 2 studies. young women [12, 635]. 12 months of treatment 12% of ● One study reported a significant – 10 % of patients with dysmenorrhea women still experience dysmenor- reduction in women reporting ab- suffer severely under this condition rhea vs 63% pretreatment) [204]. sences from work or school with [148]. ■ An open trial of a low dose combined OC therapy. – According to Schiøtz et al. (2007) combined OC in 100,000 wo- Low-dose OC: [581] dysmenorrhea is a widespread men showed that 65% of first – Data from randomized controlled tri- female problem that causes reduced time users of oral contraceptives als (RCTs) [248], cross-sectional sur- quality of life, a need for medical with pre-existing dysmenorrhea veys [463] and a non-comparative treatment, and absence from school experienced relief [60]. trial [409] support the value of OCs, or work. ■ Studies with chlormadinone ac- including those with low dosage, in – A recent Canadian study found that etate 2 mg/30 µg EE include the reducing the pain associated with 60% of menstruating women had pri- BEDY-study (Belara evaluation menstrual periods. mary dysmenorrhea with 51% report- on Dysmenorrhea) [22], – In a Cochrane review last updated in ing limitations of daily activities and CARED-study (Chlormadino- 2004, [530] no conclusions could be 17% reporting absenteeism; 60% had ne acetate/EE reduces emo- drawn as to the efficacy of currently moderate or severe pain [74]. tional dysbalance) [54] and used combined OCs, which use lower Etiology: TeeNis-study (Teenager non- estrogen doses. – The pain of dysmenorrhea arises from interventional study) [251]. – However, a recent study showed that the release of prostaglandins, which low dose (20 µg) OCs are also effec- cause an increase in myometrial ac- Higher dose OC: tive [146]. tivity [432]. – Formerly used higher dose OCs have Progestins: Treatment options been reported to provide effective – Various trials done for drug registra- Non-hormonal treatment [271] pain relief for 70–80% of women tion showed a reduction of menstrual – Non-steroidal anti-inflammatory with primary dysmenorrhea [432, pain for all progestins on the market drugs (NSAIDs) are effective in re- 236, 463]. when used in a combined oral contra- lieving the pain of primary dysme- – A Cochrane review in 2001 last up- ceptive. norrhea [18]. NSAIDs can have side dated in 2004, [530] concluded that – Several studies using chlormadinone effects, i.e. , dyspepsia, peptic medium and high dose OCs are effec- acetate-containing COCs (chlormadi- ulcer, and diarrhea [565]. For patients tive in relieving dysmenorrhea, but none acetate 2 mg/EE 20 µg) have who cannot take the more common that proof was lacking for the modern shown a high and significant reduc- NSAIDs, or for whom they are inef- low dose OCs. In this systematic re- tion of dysmenorhea and restrictions fective, a COX-2 inhibitor may be view randomized controlled trials at work, along with an increase in lei- prescribed [88]. One study indicated were analyzed comparing combined sure and sporting activities up to 83% that conventional therapy with OCs with other combined OCs, pla- in 2140 women each receiving a 2 mg NSAIDs „provides symptomatic re- cebo, no treatment or treatment with chlormadinone/30 µg EE COC oral lief but has increasing adverse effects non-steroidal anti-inflammatory contraceptive: BEDY-study (Belara with long-term use“ [352] another in- drugs (NSAIDs) for the treatment of evaluation on Dysmenorrhea) [22], dicated that long-term use of NSAIDs primary dysmenorrhea. A total of 5 CARED-study (Chlormadinone ac- has “severe adverse effects” [497]. trials were included; 4 of these were etate/EE reduces emotional disba- – Other treatment regimens include combined in a meta-analysis. All of lance) [54] and TeeNis-study (Teen- acupuncture, acupressure, and Chi- the trials included combined OCs ager non-interventional study) [251]. nese and Japanese herbal with > 35 µg of estrogen (80 µg of Regimen: etc. See the following reviews [149] mestranol in two trials, 50 µg mestra- – In a Cochrane update Wong et al. [529]. nol in one trial, and 50 µg of estrogen (2009) [721] found only limited evi- Oral hormonal contraceptives in two trials) and first- or second-gen- dence for pain improvement with the ● Combined OCs were used to treat eration progestins, compared to pla- use of the OCP (both low and medium dysmenorrhea since their introduc- cebo: dose estrogen) in women with dysme- tion in 1960. ● Meta-analysis results showed the norrhea. ● Several studies [432]; [236] have combined OCs to be more effec- (Note by the authors: this is in con- documented that combined oral tive than placebo for pain relief trast to clincial evidence and all trials contraceptives (OCs) relieve dys- (OR 2.01, 95% CI: 1.22–3.33), al- with chlormadinone acetate-contain- menorrhea by reducing menstrual though the difference was non-sig- ing OCs).

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No differences among the various OC none acetate 2mg/30 µg EE in pa- Summary: preparations were evident. tients with dysmenorrhea. Incidence: About 10% of all fertile Long cycle (“off label”): A reduction of women suffer from menorrhagia, de- dysmenorrhea can also be achieved us- – OC regimen: A Cochrane analysis fined as a menstrual blood loss of ing COC in a long cycle. found no evidence of differences > 80 ml. The prevalence of menorrhagia among the various OC preparations increases with increasing age. Summary: studied. The “off label” use of long Clinic: Excessive blood loss may lead to Disease: Dysmenorrhea often used cycles is also beneficial. iron deficiency anemia and ultimately synonymously with menstrual cramps necessitate hysterectomy is the commonest form of menstrual dis- 2.3.2.2. Menorrhagia Combined oral contraceptives: order. Prevalence: Approximately 10% of all – Several studies demonstrate that low– Prevalence: 50–90% among young fertile women suffer from menorrhagia, dose OCs reduce menstrual blood women. defined as a menstrual blood loss of loss and are effective in the treatment > 80 ml. The prevalence of menorrhagia of menorrhagia. Treatment options: increases with increasing age. – Although monthly menstruation is Non-hormonal treatment: Non-ste- Clinical consequences: Excessive natural and normal, it is not necessar- roidal anti-inflammatory drugs; other blood loss may lead to iron deficiency ily beneficial for all women. When in- treatment regimens include acupunc- anemia and ultimately necessitate hys- dicated, menstruation can be mini- ture, acupressure, and Chinese and Japa- terectomy [222]. mized with safe and widely available nese herbal medicines. See reviews forms of hormonal contraception. [149, 529]. Therapeutic effect of OC: Note: – Menstrual blood loss has been re- Users of the levonorgestrel-containing Hormonal treatment with combined duced by approximately 50% in both IUS benefit strongly from the shorter, oral contraceptives: users of high-dose OCs [487, 488], lighter, and pain-free menstrual periods – Mode of action: Combined oral con- and low-dose OCs [188, 409]. associated with this contraceptive method. traceptives (COCs) alleviate dysme- – Larsson et al. (1992) [409] showed a norrhea by reducing menstrual pros- reduction of menstrual blood loss for 2.3.2.3. taglandin release thereby preventing low-dose OCs in a non-comparative Definition of the disease: Endometrio- abnormal uterine contractility leading trial with 20 women and in a ran- sis occurs when excess endometrial tis- to reduced uterine blood flow and domized trial involving 45 women sue grows in other areas of the body (i.e., ischemic pain. with menorrhagia who were treated ovaries, fallopian tubes, and other or- – Estrogen dosages: during an 8-cycle crossover treatment gans in the pelvic region). ● Medium and high EE dose for- trial with mefenamic acid or napro- Symptoms: Symptoms include dysme- mulations (30–50 µg): Several xen or a low-dose OC or norrhea, dyspareunia (painful sex), and studies have shown a high and sig- [188]. pelvic or lower abdominal pain. nificant reduction of dysme- In a US-american randomized con- Prevalence: 10–20 % of American wo- norrhea and restrictions at work, trolled trial involving 201 women men of childbearing age develop endo- along with an increase in leisure with menorrhagia and dysfunctional metriosis (NIDCD-endometriosis); up to and sporting activities in up to 80% bleeding, a low dose OC containing 2 million women in the UK [331]. of all patients with dysmenorrhea EE 35 µg and triphasic norgestimate Treatment options: for medium and high EE dose for- was found to cause a significant re- – Targets: Potential targets for treat- mulations. duction in menstrual blood loss (87% ment are suppression of the growth of ● Low dose EE formulations in OC users versus 45 % in placebo endometrial implants, relief of pain (≤ 20 µg): In a Cochrane review users) during OC use [145]. and restoration of fertility. last updated in 2004, Proctor et al. – In a Cochrane review last updated in – Surgical treatment: Laparoscopy, (2001) [530] could not draw any 2004, Iyer et al., [345] reviewing surgical removal of adhesions, biopsy conclusions as to the efficacy of available literature in an attempt to and removal of endometrial implants currently used combined OCs, determine the effectiveness, adverse is usually the first treatment option. which use lower estrogen doses. In effects, and cost-effectiveness of – Postoperative treatment: Can be contrast, a study by Davis et al. combined OCs vs other treatments in treated surgically and/or with hormo- (2005) [146] showed that low dose reducing menorrhagia, found only nal drugs, including OCs or gonado- (20 µg) OCs were also effective. one small cross-over study comparing tropin-releasing hormone mefenamic acid, naproxen, low dose (GnRH agonists). Since symptoms – Progestins: danazol and a combined OC. No dif- terminate during pregnancy, high Various trials done for drug registra- ferences were observed among the dose progestins are initially used. tion showed a reduction of menstrual various groups. Women taking com- Low dose OCs and injectables with pain for all progestins on the market bined OCs had a 43% reduction in depot medroxyprogesterone acetate when used in a combined oral contra- menstrual blood loss, however, due to (DMPA) are also treatment options ceptive. the very small number of cases (n = 6) [339]. Furthermore, since 2010 Intensive studies have been done in- no conclusion can be drawn from this Dienogest has been approved for use vestigating the effect of chlormadi- Cochrane review [339]. in the treatment of endometriosis.

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– Medical treatment: The choice of efit from the shift to a continuous ad- – Since 2010 dienogest (Visanne®/Bayer medical treatment plays a role in the ministration. A monophasic OC (de- HealthCare) 2 mg/day; orally) can be therapeutic strategy when adminis- sogestrel 0.15 mg and EE 0.02 mg) used in patients with endometriosis. tered over a prolonged period of time. was prescribed continuously to 50 pa- Combined oral contraceptives: Given their good tolerability, minor tients with dysmenorrhea relapsing Oral hormonal contraceptives: metabolic effects and low cost, con- after conservative surgery for en- – The efficacy of combined OCs in the traceptive steroidal preparations must dometriosis and not responding to the treatment of pain-related endometrio- therefore be considered drugs of cyclic use of the same OC [687]. Dur- sis is not conclusive. In an update choice and are currently the only safe ing the 2-year study period, 38% of 2003 of a Cochrane review by Moore and economic alternative to surgery women reported amenorrhea, 36% et al. (2000) [466] clinical trials were [653]. Drugs used in the treatment of spotting and 26% breakthrough reviewed, assessing the effectiveness, endometriosis are not cytoreductive bleeding. The mean score of men- adverse effects, compliance, and cost- [526]. Quiescent implants have been strual pain, evaluated according to effectiveness of combined OCs for demonstrated in nearly all women a 100–mm visual analogue scale, the treatment of painful symptoms as- treated with danazol, gonadotrophin- showed a reduction from 75 ± 13 to sociated with the diagnosis of en- releasing hormone agonists and pro- 31 ± 17. Moderate or severe side dometriosis, compared to placebo, no gestins. Upon restoration of ovulation effects were reported by 14% of the treatment, other medical therapies, or and physiological levels of estrogens, women. conservative surgical treatment. both the eutopic and ectopic en- Progestins – pharmacological actions: However, only a single trial compar- dometrium resumes its metabolic ac- – Progestins may prevent implantation ing a combined OC with a GnRH ana- tivity. As a consequence, medical and growth of endometrium by inhib- logue met inclusion criteria [147, therapy is symptomatic and pain re- iting expression of matrix metallo- 339]. lapse at treatment suspension is the proteinases and angiogenesis. Several In this trial, the combined OC was rule [688]. anti-inflammatory and in vivo less effective in relieving dysme- – Drugs to be administered only for effects of progestins may reduce the norrhea; no difference was noted re- some months due to poor tolerability, phlogistic status generated by the garding relief of dyspareunia or non– severe metabolic side effects or high metabolic activity of the ectopic en- menstrual pain. Adverse effects var- cost, do not greatly benefit women dometrium and the consequent im- ied based on the treatment option. with symptomatic endometriosis mune response. Due to the limited data available, [685]. – Moreover, , decidualisa- more research is needed to support – Progestins and estrogen-progestins tion, amenorrhoea and the establish- the effect of combined OCs for pain are effective in the control of pain ment of a steady estrogen-progestin associated with endometriosis, [339]. symptoms in approximately three out milieu contribute to disease quies- – Progestins: Recently a mono-therapy of four women affected by endome- cence. with dienogest (2 mg/day) received triosis. Their effect does not seem to approval for treatment of endometrio- be inferior to that of other drugs used Summary: sis. Previously, chlormadinone ac- for treating the disease [466, 525, Disease: Endometriosis occurs when ex- etate (2 mg/day) lost its approval in 688]. Different compounds can be cess endometrial tissue implants in other Germany for endometriosis; further- administered by the oral [119, 683, areas of the body (i.e., ovaries, fallopian more, lynestrenol has been with- 687] intramuscular [684], subcutane- tubes, and other organs in the pelvic drawn from the market. Desogestrel ous, intravaginal and intrauterine region) causing dysmenorrhea, dys- (75 µg/day) using 1–2 tablets con- route [178, 682, 686] with specific pareunia, and pelvic or lower abdominal tinuously can only be used “off-la- advantages and disadvantages. pain. bel”. Contraceptive progestins alone or – EE-Dosage: Low-dose OCs used in a combined with estrogens are gener- Prevalence: 10–20 % of American continuous application mode in pa- ally well tolerated, have a more lim- women of childbearing age develop en- tients with dysmenorrhea relapsing ited metabolic impact as opposed to dometriosis (NIDCD); up to 2 million after conservative surgery for en- danazol or GnRH analogues, are in- women in the UK [331]. dometriosis and not responding to the expensive and may be used on a long– cyclic use of the same OC showed a term basis [466, 525]. Treatment options: reduction of the pain scores by about Cyclic hormonal contraception is the – Potential targets for treatment are 50% [687]. only treatment for endometriosis that suppression of the growth of endome- – Regimen: no data are available as to permits a monthly uterine bleeding. trial implants, relief of pain and resto- the efficacy of different regimens in Dysmenorrhea is known as the most ration of fertility. patients with endometriosis. frequent and most severe complaint in – Endometriosis is treated surgically women with this disease. The symp- and/or with hormonal drugs, includ- 2.3.2.4. Premenstrual Syndrome (PMS) tom may therefore not subside com- ing OCs or -releasing and Premenstrual Dysphoric Disorder pletely during administration of an hormone agonists (GnRH agonists). Premenstrual syndrome (PMS) OC. – Combined oral contraceptives are a Definitions: PMS has been defined as Women affected by dysmenorrhea treatment option. ‘the cyclic recurrence in the luteal phase during cyclic use of an OC may ben- of the menstrual cycle of a combination

72 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills of distressing physical, psychological ciently severe to carry its own DSM-IV offering some relief [395, 709]. Never- and/or behavioral changes of sufficient diagnosis; it is typically treated with theless, controlled clinical trials are severity to result in deterioration of in- antidepressants. necessary. terpersonal relationships and/or interfer- Oral contraceptives and PMDD: ence with normal activities [542]. It is – The progestin drospirenone is a de- Premenstrual dysphoric disorder estimated that women with these symp- rivative of that binds (PMDD): Premenstrual dysphoric disor- toms comprise 3 to 5% of the female to receptors, causing ex- der (PMDD) is a form of PMS suffi- population in their reproductive years cretion of excess sodium and water in ciently severe to receive its own DSM- [355, 547, 723]. exchange for potassium, thus reduc- IV classification. ing bloating, breast tenderness, and The only OC with approval only in the Prevalence: weight gain. Thus drospirenone-con- US for treating PMDD is the 24+4 regi- – During the reproductive years, up to taining OCs may be expected to have men with drospirenone. 80–90% of menstruating women will a beneficial effect on the physical For additional information about treat- experience symptoms (, symptoms of PMS and PMDD. ment options for PMS see [286]. bloating, acne and constipation) that – OC preparation containing drospire- forewarn them of impending men- none with diuretic properties has un- 2.3.2.5. Acne struation, so-called premenstrual dergone the most rigorous testing in Disease: Acne is a common skin condi- molimina. normal women and women with tion related to an increased rate of sebum – Over 60% of women report swelling strictly defined PMDD. Though the production, predominantly controlled or bloating [412], although objective evidence supporting a role for fluid by androgenic sex hormones. documentation of weight gain is lack- retention as an etiologic component Prevalence: Acne affects up to 40– ing in most of these women [175]. of PMS is lacking [175] many women 90% of adolescents and teens [371, – Cyclic breast symptoms affect 70% of are distressed by feelings of bloating 413], 10% of adult women [541, 655] women with 22% reporting moderate and edema. In an RCT involving 82 and can persist into adulthood in 53% to extreme discomfort [4]. women with PMDD, patients treated of women [112, 212]. Women are more – Available data suggest that as many as with the drospirenone and EE oral likely to report having acne and to have 30–40% of these women are suffi- contraceptive had fewer luteal phase it persist into later years with a mean ciently bothered by symptoms to seek symptoms than those treated with pla- duration in affected adult women of 20 relief. cebo, although between group differ- years [594]. ences were statistically significant Etiology: are related to the Oral contraceptives and PMS: only for appetite, acne and food development of acne, whereas many – Observational studies in the 60s and cravings, p = 0.027 [194]. The dros- combined oral contraceptive pills, and in 70s suggested that premenstrual com- pirenone OC offers relief for some particular those which contain anti-an- plaints were reduced in many oral physical and some psychological drogens are clearly beneficial for the contraceptive users [468] although manifestations of PMS and may im- treatment of acne. symptoms be exacerbated by OC use prove health-related quality of life in some women. [55, 195]. For prolonged treatment of Treatment options: – The first systematic studies to exam- patients with moderate symptoms, Dermatological treatment options: ine the effects of the OC on PMS OC is preferable, more acceptable According to the guidelines of the Ger- found little difference in PMS symp- and cheaper than selective serotonin man Dermatological Society [478], the toms between OC users and nonusers reuptake inhibitors, but in the case of first choice treatments for acute acne in [36], nor were there significant differ- severe symptoms associated with men and women according to acne type ences between agents with differing PMDD more specific treatment is re- are as follows: progestational potencies [13]. Mono- quired. phasic and triphasic preparations – Comedonal acne: topical retinoids. showed similar rates of symptomatol- Summary: – Mild papular/pustular acne: fixed or ogy [213]. Premenstrual syndrome (PMS): Dur- sequential combinations of BPO – Until now no oral contraceptive has ing the reproductive years, up to 80– (benzoyl peroxide) and topical been approved worldwide for treat- 90% of menstruating women will expe- retinoids or topical antibiotics. ment of PMS, but the off-label use of rience symptoms (breast pain, bloating, – Moderate papular/pustular acne: oral long-cycle, combined oral contracep- acne and constipation) that forewarn antibiotics plus BPO or topical tives is offering some relief [392, them of impending menstruation, so- retinoids, or in a fixed combination. 709]. Nevertheless, controlled clini- called premenstrual syndrome (PMS) – Acne papulo-pustulosa nodosa and cal trials are necessary. Available data suggest that as many as acne conglobata: oral antibiotics plus – For additional information about 30–40% of these women are suffi- topical retinoids plus BPO or oral treatment option of PMS see [286]. ciently bothered by symptoms to seek isotretinoin. relief. – For maintenance treatment: topical Premenstrual dysphoric disorder Until now no oral contraceptive has retinoids or its combination with (PMDD) been approved worldwide for treatment BPO. Particular attention should be Definition: Premenstrual dysphoric dis- of PMS, but the off-label use of long- paid to compliance and quality of order (PMDD) is a form of PMS suffi- cycle, combined oral contraceptives is life.

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Note: According to this guideline com- comparing the effects of COCs on after 9 cycles as compared to the bined oral contraceptives, either alone or acne with those of other therapies. latter product (63% and 59 %, re- in combination, are no first line therapy ● The search yielded 25 trials: 7 pla- spectively). for any type of acne. This, however, does cebo-controlled trials made 4 dif- In a double-blind study, Thorney- not reflect the situation observed in ferent comparisons, 17 trials made croft et al. (2004) [656] compared gynecological outpatients in clinical 13 comparisons between 2 differ- the efficacy and tolerability of practice. ent COC regimens, and 1 addi- a combined oral contraceptive Global guidelines for acne have been tional trial compared a COC to an containing 30 µg EE and 3 mg summarized by the Geneva Medical antibiotic. COCs reduced acne le- drospirenone (EE/DRSP; Yasmin) Foundation [310]. sion counts, severity grades and with a triphasic preparation con- self-assessed acne compared to taining 35 µg EE and 0.180, 0.215, Combined oral contraceptives placebo. Differences in the com- 0.250 mg norgestimate (EE/NGM; – Various studies have proven the effi- parative effectiveness of COCs Pramino, also known as Ortho Tri- cacy of COC, especially those con- containing varying progestin types Cyclen) in the treatment of acne taining anti-androgenic progestins, and dosages, were less clear, how- vulgaris. The preparation contain- for the primary treatment of acne vul- ever. ing EE/DRSP was superior to EE/ garis. ● COCs that contained chlormadi- NGM in reducing the total lesion – Mechanism: Combined OCs may none acetate or cyproterone ac- count (–3.3% in favor of EE/DRSP prevent acne through several mecha- etate improved acne better than [95% CI, –6.5 to –0.1; p = 0.020]) nisms: levonorgestrel, although this ap- and for the investigators’ assess- ● COCs suppress luteinizing hor- parent advantage was based on ment of the therapeutic effect on mone (LH), and cause decreased limited data. facial acne (+3.6% in favor of production of androgens, includ- ● A COC with cyproterone acetate EE/DRSP [95% CI, 0.8 to 6.3; ing free testosterone. might result in better acne out- p = 0.006]). The 2 preparations ● The estrogen component of COC comes than one with desogestrel; were comparable in reducing the increases SHBG ( bind- however, the three studies compar- inflammatory lesion count. In con- ing globulin) levels and decreases ing these COCs produced conflict- clusion, the combined oral contra- serum free testosterone by binding ing results. ceptive EE/DRSP provides an ef- more circulating testosterone. ● Likewise, levonorgestrel showed a fective treatment option in women ● Anti-androgenic progestins block slight improvement over deso- with mild to moderate acne. receptors and inhibit the gestrel in treating acne in one trial, ● 24+4 regimen: According to two 5alpha-reductase that con- but a second trial found that the multicenter, double blind, rando- verts testosterone to dihydrotesto- COC groups were similar. mized, placebo-controlled studies sterone in the hair follicles and – In conclusion the authors found that [439], 889 subjects, ages 14 to 45 skin [25]. four COCs (levonorgegestrel [420, years, with moderate acne received – Progestins: The effect of OCs on 655] norethindrone [438], norgesti- drospirenone/ethinyl estradiol acne depends on their progestin activ- mate [430, 541] drospirenone [378, (YAZ®) or placebo for six 28 day ity. Theoretically progestin domi- 439] evaluated in placebo-controlled cycles [322]. The primary efficacy nance would exacerbate acne, where- trials are effective in reducing inflam- endpoints were the percent change as estrogen dominance would exert an matory and non-inflammatory facial in inflammatory lesions, non-in- anti-androgenic effect on the seba- acne lesions. No significant differ- flammatory lesions, total lesions, ceous glands. Anti-androgenic proge- ences were found between COC types and the percentage of subjects with stins such as cyproterone acetate, in their effectiveness for treating a “clear ” or “almost clear” rating chlormadinone acetate, diengest, and acne. How COCs compare to alterna- on the Investigator’s Static Global drospirenone produce the best thera- tive acne treatments is unknown since Assessment (ISGA) scale on day peutical results as shown in compara- limited data were available regarding 15 of cycle 6. YAZ® was superior to tive studies in the treatment of acne in this question. placebo in the mean percent women: change from baseline on all 3 pri- ● Cyproterone acetate [115, 173, – Drospirenone: mary acne efficacy measures and 197, 465] ● 21+7 regimen: A number of trials the probability that skin was ● Chlormadinone acetate [726] evaluated drospirenone-containing “clear” or “almost clear” on an in- ● Dienogest [185, 467, 502] OCs for the treatment of acne: vestigator-rated global scale. ● Drospirenone [678] Van Vloten et al (2002) [678] ● Norgestimate [541] compared 30 µg EE/3 mg dros- – Dosages and regimen: The dosage of but also pirenone (Yasmin) to a combined EE (20–50 µg) in the OC and the regi- ● Desogestrel [696] OC containing 35 µg EE/2 mg men (monophasic, triphasic, 21+7, ● Gestodene [515] cyproterone (not available in the 24+4) followed are less relevant than ● Norethindrone [438] U.S., but used elsewhere for con- the type of progestin used. – In a Cochrane review Arowojolu et traception/acne treatment). Yasmin – Management of acne treatment: al. (2009) [26] searched for ran- produced a greater decrease in For management of mild to moderate domized placebo-controlled trials median total acne lesion count acne in women, the combination of

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OCs with topical medications such as men (monophasic, triphasic, 21+7, which often contains micro- or macro- retinoids and antibacterial agents in 24+4) followed are less relevant than cysts and adenosis with the development standard clinical practice is likely to the type of progestin used. of new lobular or ductal structures. The be successful. Such combination – VTE–risk: When using COC with epithelium may display metaplasia into therapy should lead to more rapid and cyproterone acetate a higher possible apocrine epithelium such as found in greater improvement given the rate of venous thromboembolism sweat glands, or hyperplasia, with or synergistic mechanisms of these dif- must be considered [422, 674]. without atypia. ferent treatments. Future studies are – For management of mild to moderate The benign breast tumor fibroadenoma needed to evaluate the outcomes of acne in women, the combination of arises from the single breast lobule, usu- such combination therapy [636]. OCs with topical medications such as ally as a well-defined mass containing an retinoids and antibacterial agents in epithelial and a stromal component. Summary: standard clinical practice is likely to Fibroadenomas appear to result from Prevalence: Acne is a common skin be successful. Such combination the- hyperplasia and distortion originating in condition related to an increased rate of rapy should lead to more rapid and a single lobule involving normal epithe- sebum production, predominantly con- greater improvement given the lial components and abnormal stromal trolled by androgenic sex hormones. It synergistic mechanisms of these dif- components. The age of maximum inci- affects up to 40–90% of adolescents and ferent treatments. Future studies are dence is between women aged 20–25 teens [371, 413], 10% of adult women needed to evaluate the outcomes of years. The histological changes are con- [541, 655] and can persist into adulthood such combination therapy [636]. fined to the stroma while the epithelial in 53% of women [112, 212]. Women Dermatological treatment options: cells are normal. are more likely to report having acne and – According to the guidelines of the Prevalence: The cumulative incidence to have it persist into later years with a German Dermatological Society of biopsy-proven BBD estimated from mean duration in affected adult women [478] the first choice treatments for epidemiological studies is 10–20% [107, of 20 years [594]. acne do not include oral contracep- 183, 354, 494]. Combined oral contraceptives tives even with anti-androgens. – Mode of action: COCs suppress – Global guidelines for acne have been Treatment options: (LH) and cause summarized by the Geneva Medical – A number of studies published in the decreased production of androgens, Foundation [310]. 1970s and 1980s [209, 456] sug- including free testosterone. The gested that OCs used in the 1970s ex- estrogen component of COCs in- 2.3.2.6. Benign Breast Disease ert a protective effect against benign creases sex hormone binding glo- Even though the use of combined oral breast disease. In many of these stud- buline (SHBG) levels and decreases contraceptives is associated with an in- ies, however, the diagnosis of BBD serum free testosterone by binding creased risk of breast cancer [647] the was not confirmed by biopsy but more circulating testosterone. Anti- risk of benign breast disease (BBD) may based on self-reporting. The three androgenic progestins block andro- be reduced [72, 366]. more recent studies have demon- gen receptors and inhibit the enzyme There is still no consensus on the associ- strated somewhat inconclusive re- 5a-reductase, which converts testo- ated risk of breast cancer and benign sults. One small prospective study of sterone to in the breast diseases, exept benign tumors OC users in Greece suggested a re- hair follicles and skin. with atypical change. duced incidence of BBD diagnosed – Anti-androgenic COC: COCs with Definition of the disease: The term be- by mammography and ultrasound progestins with anti-androgenic ac- nign breast disease describes a wide [666]. One hospital-based case-con- tivity (cyproterone acetate, chlorma- range of non-malignant disorders of the trol study from France [89] of women dinone acetate, dienogest, drosprire- breast. Despite numerous attempts, there with BBD confirmed by biopsy dem- none, norgestimate [only US approval is no internationally agreed classifica- onstrated a reduced risk among OC for acne]) are highly effective and tion of these breast disorders. The only users. This result was restricted to lead to an improvement of acne vul- genuine point of agreement seems to be non-proliferative disease and only to garis lesions in 80% after 3 months that the term excludes malignant breast pill use before the first full term preg- and > 90% after 6–12 months treat- pathology. The two main conditions of nancy. In contrast a case-cohort analy- ment. BBD are fibrocystic disease and fibro- sis within a large cohort of Canadian – A recent systematic review reported adenoma [209]. women undergoing breast screening on six placebo-controlled trials (nore- Fibrocystic breast disease is an ill-de- and biopsy [552] showed an inverse thindrone, levonorgestrel, norgesti- fined condition characterized by the relationship between OC use and pro- mate, drospirenone) that evaluated presence of palpable lumps in the breast. liferative BBD without atypical cells. oral contraceptive treatment for They usually present with pain and ten- In this study, there was no association women with moderate to severe acne derness of the breast. The lumps and the between BBD with atypical cells and Arowojolu et al. (2009) [26] showed related symptoms fluctuate with the OC use. Modern oral contraceptive that OCs reduced acne lesion counts menstrual cycle. The maximum inci- pills contain lower doses of both, and severity as assessed by clinicians dence is seen among women in their estrogen and progestin, than those and the patients themselves. early forties, the symptoms tend to wor- used in the 1970s. The risk reduction – Dosages and regimen: The dosage of sen until the menopause. The histologi- for BBD may be diminished or even EE (20–50 µg) in the OC and the regi- cal changes affect the breast epithelium, lost with lower doses of steroids.

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– All the research suggesting a benefi- (Source statistic for calculation: “10– cally develop after menarche and re- cial effect of the combined pill on be- 20% women [NWHIC]”). Uterine leio- gress after menopause, implicating nign breast disease emerges from ob- myomas occur in 20% to 25% of women estrogen as a promoter of leiomyoma servational studies with potential of reproductive age and reportedly affect growth [531]. bias. One form of bias may be the un- three times as many black women as – In earlier studies it has been sug- derestimation and underdiagnosis of white women. The risk of malignant gested that OC use is associated with the BBD. It is well known that BBD is transformation of a leiomyoma into a a reduced risk of fibroids [503, 564]. more common among better-edu- leiomyosarcoma is only 0.1% or less However, in these early studies, the cated women of higher socioecono- [531]. diagnosis was limited to women with mic status leading to a selection bias surgical confirmation of fibroids. [209]. The finding that BBD is less Etiology: The clear etiology of uterine – The postulated beneficial effect of common in obese women suggests a leiomyomas is still unknown, but steroid OC on growth inhibition of fibroids detection bias [209]. At least one hormones, including estrogen and pro- needs to be proven for modern low study demonstrated a prescribing bias gesterone, and several growth factors, dose formulations and regimens. [348] suggesting that women with a including epidermal growth factor, have history of BBD are less likely to be been implicated as regulators of the 2.3.2.8. Benign Ovarian Tumours prescribed oral contraceptives. In ad- growth of leiomyomas. They typically Definition of the disease: Benign dition to the multiple problems with develop after menarche and regress after tumors of the ovaries represent a com- bias, the studies available suffer from menopause, implicating estrogen as a plex entity of non-malignant ovarian rather poor quality, small numbers of promoter of leiomyoma growth [531]. tumors (e.g. functional and dysfunc- cases, and variability in the definition Effect of COC: It has been suggested tional ovarian cysts, serous and muci- of the disease itself. On the other hand that OC use is associated with a reduced nous adenoma, teratoma and endome- there is good evidence that OC use risk of fibroids [503, 564]. However, in trioma). stimulates epithelial proliferation these early studies, the diagnosis was Incidence and Prevalence: [313] in the breast [17, 344] casting some limited to women with surgical confir- – Ovarian cysts occur in 30% of fe- doubt on the biological plausibility of mation of fibroids. Two large studies males with regular menses, 50% of a protective effect on benign disease. from the USA in which fibroids were di- females with irregular menses, and agnosed either at hysterectomy or by ul- 6% of postmenopausal females Summary: trasound [451, 720] suggest no clear pat- – Polycystic ovary syndrome occurs in Disease: BBD is a general term, which tern of association, although both report approximately10% of women in in- incorporates a wide spectrum of non- a weak association between fibroids and dustrialized countries. malignant disorders of the breast tissue. use of the combined pill before the age – The majority of ovarian cysts are be- Incidence: The cumulative incidence of of 17. A smaller study of 335 randomly nign (non-cancerous). biopsy-proven BBD as estimated from selected Swedish women aged 25–40 re- – The annual incidence of ovarian can- epidemiological studies is 10–20% [107, ported a rather low prevalence of (ultra- cer is 15 cases per 100,000 women. 183, 354, 494]. sound detected) fibroids (5.4%; 95% CI 3.0–7.8%) in contrast to earlier studies, Treatment options: Combined oral contraceptives: which suggested a prevalence of 20 to Combined oral contraceptives: – Although there is some evidence that 25% in women over age 30 [56]. Al- – The use of a combined oral contra- high-dose oral contraceptives may re- though the sample size was too small to ceptive is associated with a reduced duce the risk of BBD, there are sig- detect an effect of the OC on fibroids, risk of ovarian cancer. By analogy it nificant problems with bias, study de- uterine size was significantly smaller has been suggested that the risk of sign and interpretation [71]. among women taking a combined oral benign ovarian tumors is also re- – An increased risk of BBD has never contraceptive pill than in women with duced. been demonstrated, whereas the benefi- natural cycles. The authors suggest that – Current-users: A number of studies cial effects of oral contraceptives on the high prevalence of OC use might ex- have shown a theoretically suspected the breast tissue may be overestimated. plain the low prevalence of fibroids in reduced risk of functional ovarian their study (selection bias). cysts while taking oral contraceptives 2.3.2.7. Uterine Fibroids/Leiomyomas of since ovulation is inhibited [261]. the Uterus Summary: – Ever-users: However, a large case– Definition of the disease: Uterine fi- – Uterine leiomyomas occur in 20– control study from the USA demon- broids or leiomyomas are non-malignant 25% of women of reproductive age strated that use of the combined pill at tumors that originate from the myo- and affect 3 times as many black any time was associated with a de- metrium. They present as single solid women as white women. creased risk of non-follicular benign tumors or more often in multitude. Fi- – The etiology of uterine leiomyomas is tumors, including serous and muci- broids can cause different symptoms due unknown, but steroid hormones, in- nous adenoma, teratoma and en- to their location in the uterine wall (sub- cluding estrogen and progesterone, dometrioma (OR 0.79, 95% CI 0.6– mucosal, intramural or subserosal). and several growth factors, including 1.05) [704]. The reduction in risk was Prevalence: In 10–20% of all women epidermal growth factor, have been associated with duration of use. leiomyomas of the uterus can be diag- implicated as regulators of leio- – Although OC use is associated with a nosed, i.e. 13.6 million people in the USA. myoma growth. Leiomyomas typi- lower prevalence of benign ovarian

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tumors, prospective studies have Chlamydia justed risk is not significant, it corre- failed to show that the use of OC can Prevalence: sponds to the risk estimates from the prevent the development of ovarian – Currently, the most prevalent infection earlier studies and underlines the cysts or treat existing ovarian cysts in Western Europe is Chlamydia need for promoting barrier methods [650]. trachomatis (CT). The prevalence of of contraception [472]. This change Chlamydia trachomatis infection in attitude towards prevention of Summary: among asymptomatic European wo- pregnancy and sexual transmitted in- Disease: Various entities of benign ovar- men ranges from 1.7 to 17%, depend- fection is promoted by the term „dou- ian tumors can be differentiated histo- ing on the setting [714]. ble dutch“ – dual protection with bar- logically and due to diverse etiolo- – The difference in prevalence is deter- rier methods and hormonal contra- gies. mined mainly by age, rather than by ception [77]. Incidence and Prevalence [313]: Ovar- clinical setting. The highest preva- ian cysts occur in 30% of females lence is detected in teenagers and the It seems to be clear that prevention of with regular menses, 50% of females lowest in women over the age of 30. cervical infection is not a non-contra- with irregular menses, and 6% of – Prevalence rates may be as high in ceptive benefit from OC use. The de- postmenopausal females. Polycystic men, although not necessarily follow- velopment and implementation of ovary syndrome occurs in approxi- ing the identical age distribution. This routine HPV-immunisation in girls mately 10% of women of reproduc- aspect is one of the reasons why and young women complements the tive age (“Polycystic Ovary Syn- screening initiatives solely focusing preventive strategies. drome”). The majority of ovarian on women are questioned [180]. cysts are benign (non-cancerous). Combined oral contraceptives: Pelvic inflammatory disease Combined oral contraceptives: – The data in hand about Chlamydia – Although earlier studies suggested a – OC use has been associated with a trachomatis infection are very in- decrease in hospitalizations for pelvic lower prevalence of benign ovarian homogenous and of varying quality. infection, in other studies oral contra- tumors [566] mainly due to an inhibi- Some studies were cross-sectional in ceptive use was associated with an in- tion of ovulation. design, some used inappropriate test creased risk of chlamydial infection – Reduced risk in ever-users: A large methods for chlamydial infection and and gonorrhea [120]. case-control study from the USA most failed to control for potential demonstrated that ever-use of the confounding factors such as sexual Summary: combined OC was associated with a behavior and age. Behavior modifica- – Oral hormonal contraceptives pre- decreased risk of non-follicular be- tion due to sexual education led to a vent pregnancy but do not directly nign tumors, including serous and steadily increasing use of contracep- protect against sexually transmitted mucinous adenoma, teratoma and en- tives to prevent pregnancy and STIs. diseases. dometrioma (OR 0.79, 95% CI 0.6– Nevertheless the high prevalence of – Anyhow the cervical mucus and the 1.05) [704]. The reduction in risk was chlamydial and HPV infections and cervical barrier for ascending sperms associated with duration of use. the careless attitude towards risks and infections is altered by OCs and – No prevention or treatment of ovar- of STI, especially HIV-infection, in the risk of pelvic inflammatory dis- ian cysts: Clinical studies have failed young women are alarming. eases is decreased. to show that the use of OC can prevent – A recent observational study involv- – The epidemiological data on this as- the development of ovarian cysts or ing 814 women in the USA who were pect are not conclusive. Although ear- treat existing ovarian cysts [650]. using different methods of contracep- lier studies suggested a decrease in tives (oral contraceptives, depot hospitalizations for pelvic infection, 2.3.2.9. Sexually Transmitted Infections gestogens, or non-hormonal methods in other studies oral contraceptive use Referring to an apparently increasing of contraception) documented sexual was associated with an increased risk rate of sexually transmitted infections behavior [472]. The authors con- of chlamydial infection and go- (STIs) [62] several European govern- cluded that the use of OC was not sig- norrhea [120]. The quality of studies ments have expressed concerns about nificantly associated with an in- is inhomogenous and mostly poor. An the current poor state of sexual health creased risk of chlamydial infection observational study involving 814 [215]. or gonorrhea after adjusting for other women with different contraceptive risk factors (HR 1.5; 0.6-3.5). No as- methods in the USA could not prove Sexually transmitted infections include sociation was found between the the risk reduction for chlamydial in- more than 25 diseases transmitted via presence of cervical ectopy and infec- fection [472]. A retrospective analy- sexual activity i.e. chlamydia, HIV-in- tion either with oral contraceptive or sis of 563 women with diagnosed PID fection, , gonorrhea, syphilis, injectable contraceptive use. The risk did not give a conclusive association herpes genitalis, human papilloma virus, of acquiring Chlamydia trachomatis either between OC use or barrier candidiasis and trichomoniasis. infection during 1 year of follow-up methods [480]. In the following passage the effect of was 1.9-fold higher in oral contracep- – The protective effect on the develop- combined OC on chlamydial infections, tive users (95% CI 0.7, 4.8), com- ment of pelvic inflammatory disease hospital admission and late sequelae due pared with users of non-hormonal including hospitalizations due to OC to pelvic inflammatory disease will be contraceptive methods after adjusting use was described in publications and analyzed. for sexual behavior. Although this ad- seemed to be independent of the dos-

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age of estrogen and type of estrogen Histology: Histologically, ovarian can- prognosis is poor. The annual age ad- [495]. cer is divided into different subgroups justed mortality rate of ovarian cancer – Only the condom has been shown to such as serous, mucinous, endo- lies at about 9/100,000; the overall have a protective effect [78]. metrioid, clear cell carcinoma, Bren- 5-year survival rate of women with ner tumor, and undifferentiated carci- ovarian cancer was 45% (1996–2003) 2.3.2.10. Cancer nomas [587]. According to this re- [349]. Oral contraceptives are associated with a view serous carcinoma is the most risk reduction for ovarian, endometrial common type of ovarian cancer; it is For ovarian cancer, the 30–50% reduced and perhaps colorectal cancer. The in- usually associated with peritoneal mortality rates in countries where OC verse relation between OC use and ovar- metastases and poor survival except had long been extensively used corre- ian and endometrial cancers is one of the for meticulously staged patients with spond to 3000–5000 deaths from ovar- most consistent epidemiological find- tumors confined to the ovaries. Endo- ian cancer avoided in Europe [403, 418]. ings and in terms of public health, it is metrioid and clear cell carcinomas ac- Mortality trends: In developed coun- one of the most important examples of count for most non-serous carcino- tries young women showed a substantial large-scale chemopreventive interven- mas and more often present with low- decline in ovarian cancer mortality over tion [335, 402]. stage disease; survival for the various the last few decades. Cohort analysis of cell types is similar when stratified by trends in mortality from ovarian cancer The following analysis is based on the stage. Borderline ovarian tumors can showed that women born after 1920 – IARC monography (1999) [278] and be subdivided into benign and malig- i.e. from the generations who had used extended reviews: Cibula et al. (2010) nant . Women with typical OCs – had reduced ovarian cancer rates, [96], Mueck et al. (2010) [474], The serous borderline tumors, atypical and the downwards trend was greatest in ESHRE Capri Workshop Group proliferative serous tumors, constitute countries where oral contraceptives have (2005) [649] with kind permission by most of these patients and have virtu- been more widely utilized [335, 404]. the authors. ally 100% survival, unless invasive peritoneal implants are present. Combined oral contraceptives and The effect of COC on breast and cervical Micropapillary serous carcinomas, a risk of ovarian cancer cancer is described in section discussing less common variant, also called se- The first reports about an association be- serious adverse events. rous borderline tumor with a micro- tween ovarian cancer and oral contra- papillary pattern, and tumors with in- ceptives were published by Newhouse 2.3.2.11. Ovarian Cancer vasive implants behave similarly to et al. (1977) [483]. Incidence: low-grade invasive carcinomas. The Collaborative Group on Epide- – Second most frequent genital malig- miological Studies of Ovarian Cancer nancy of women. The worldwide inci- Risk factors (American Cancer Soci- (2008) [109] performed a metaanalysis dence for ovarian cancer is docu- ety) [10] for ovarian cancer include of data including 23,257 women with mented as 6,6/100.000, whereas the age, obesity, reproductive history, ovarian cancer and 87,303 controls from highest incidence is seen in Europe gynecologic surgery, fertility drugs, 45 epidemiological studies in 21 coun- with 13/100,000, in particular in androgens, estrogen therapy and hor- tries. The relative risk of ovarian cancer Western Europe (varying widely be- mone therapy, family history of ovar- in relation to oral contraceptive use was tween 7–19/100,000 women) [275]. ian cancer, breast cancer, or colorec- estimated and stratified by study, age, – In high-incidence areas, the lifetime tal cancer, personal history of breast parity, and hysterectomy. Overall 7,308 risk of developing ovarian cancer is cancer, talcum powder, diet, analge- (31%) cases and 32,717 (37%) controls estimated to be at 1–2%. sics, smoking, and alcohol use. had ever used oral contraceptives, for – US National Cancer Institute A high-risk situation is present in all average durations among users of 4.4 (SEER) [284]: From 2003–2007, the cases with genetic predisposition, and 5.0 years, respectively. The median median age at diagnosis for ovarian namely BRCA-1 and 2 (approx. 10% year of cancer diagnosis was 1993, when cancer was 63 years. About 1.3% are of all cases). the patient had an average age of 56 diagnosed under the age of 20 years; According to the Holden Compre- years. 3.5% between 20 and 34; 7.4% be- hensive Cancer Center, Cancer In- tween 35 and 44; 19.2% between 45 formation Service (2003) [257], pro- – Risk reduction by time of OC use: and 54; 22.9% between 55 and 64; tective factors for the development of The longer the duration of oral contra- 19.5% between 65 and 74; 18.4% be- ovarian cancer areoral contraceptives, ceptive use, the greater the reduction tween 75 and 84 and 7.8% at 85+ childbearing, breast-feeding, tubal in ovarian cancer risk (p < 0.0001). years. The age-adjusted incidence ligation and hysterectomy. – Persistence of reduced risk after rate of ovarian cancer was 12.9 per Risk factors for ovarian cancer are OC withdrawal: This reduction in 100,000 women per year. These rates summarized in the publication of risk persisted for more than 30 years are based on cases diagnosed in 2003– Riman et al. (2001). after oral contraceptive use was 2007 from 17 SEER geographic areas. ceased but became attenuated over – Successful general screening pro- Mortality: Most cases of epithelial time – the proportional risk reduc- grams for ovarian cancer do not exist ovarian cancer (EOC), which consti- tions per 5 years of use were: up to now and therapeutic options are tute 80–90% of ovarian malignancies, ● 29% (95% CI 23–34%) for OC use still limited [123]. are detected at an advanced stage. The stopped less than 10 years ago

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● 19% (14–24%) for OC use stopped cancers prevented by OC will rise significant even though smaller 10–19 years ago to at least 30,000 cases per year (19%) for years 10–20, and smaller ● and 15% (9–21%) for use stopped [48]. still (15%) 20–29 years after dis- 20–29 years previously. continuation of the OC. – Estrogen dosage: OC use during the Summary: ● Histology: OCs seem to protect 1960s, 1970s, and 1980s was associ- Incidence: Ovarian cancer is the second against nearly all types of epithe- ated with similar proportional risk re- most frequent genital tumor entity of lial and nonepithelial tumors, with ductions, although typical estrogen women. In high-incidence areas, the the possible exception of muci- doses in the 1960s were more than lifetime risk of developing ovarian nous ovarian cancer (which ac- twice those in the 1980s and later. cancer is about 1–2%. counted for only 12% of cases – Amount or type of hormones in Histology: Histologically, ovarian can- studied in the metaanalysis). OCs: One of the studies used in the cer is divided into different subgroups ● Estrogen-dosage: The Lancet Harvard analysis, the Cancer and such as serous, mucinous, endome- editorial [166] points out “the Steroid Hormone Study 1997 trioid, clear cell, Brenner, and undif- benefits of oral contraceptives are (CASH) [646], found that the reduc- ferentiated carcinomas [587]. Most independent of the preparation tion in ovarian cancer risk was the cases of epithelial ovarian cancer [estrogen dose], and vary little by same, regardless of type or amount of (EOC), which constitute 80–90% of ethnic origin, parity, family history estrogen or progestin in the COC. A ovarian malignancies, are detected at of breast cancer, body–mass index, more recent analysis of data from the an advanced stage, and the prognosis and use of hormone replacement CASH study, however, indicated that is poor. therapy.” OC formulations with high levels of Combined oral contraceptives: BRCA1/2 mutations: According to a progestin reduced ovarian cancer risk – Since combined oral contraceptives recent metaanalysis of Iodice et al. more than preparations with low pro- were first licensed nearly 50 years (2010) [343] OCs reduce the risk of gestin levels [578]. In another recent ago, birth control pills containing ovarian cancer without any evidence study, the Steroid Hormones and Re- estrogen have prevented about that recent formulations increase the productions study (SHARE) [216], 200,000 cases of ovarian cancer risk of breast cancer in women with a researchers investigated new, lower– world-wide, this estimation was pub- germline mutation in BRCA1 or dose progestins that have varying an- lished in The Lancet. Furthermore, BRCA2. drogenic properties (testosterone– without oral contraceptives, half of For more information see National like effects). They found no differ- these women would have died of Cancer Institute (US) [290, 291]. ence in ovarian cancer risk between ovarian cancer [166, 295]. Reviews and metaanalysis: androgenic and non–androgenic – The Collaborative Group on Epide- – IACR Monographs on the Evalua- COC. miological Studies of Ovarian Can- tion of Carcinogenic Risks to Hu- – Histology: The incidence of muci- cer (2008)[109] did a comprehensive mans (2009) [278] nous tumors (12% of the all ovarian meta–analysis based on prospective – Metaanalysis: Collaborative Group cancers) is affected by oral contracep- and case–control data from 45 epide- on Epidemiological Studies of tives minimally. Apart from this entity miological studies in 21 countries, Ovarian Cancer (2008) [109] the proportional risk reduction did mostly in Europe and the United – Extended reviews: Cibula et al. not vary between different histologi- States. According to the National (2010) [96] cal types [405]. Cancer Institute, US [295] the re- Further references: – Total reduction of risk and mortal- sults are as follows: – The ESHRE Capri Workshop Group ity: In high-income countries, 10 ● Ever-users: Women who had taken (2005) [649]. years use of oral contraceptives was OCs were 27% less likely to de- – National Cancer Institute (US) [295]. estimated to reduce ovarian cancer in- velop ovarian cancer. The studies cidence before age of 75 from 1.2–0.8 included 23,257 women with ovar- 2.3.2.12 per 100 users and mortality from ian cancer, 31% of whom had Disease: Uterine Cancer with the origin 0.7 to 0.5 per 100; for every 5000 taken OCs; of the 87,303 controls, in the endometrium (see histology). woman-years of use, about two ovar- 37% had taken OCs. Histology and hormonal dependency: ian cancers and one death from the ● Duration of use: The longer the Endometrial cancers are classified disease before age 75 are prevented duration of OC use, the greater is into two major histopathological enti- [48]. the ovarian cancer risk reduction ties, which are based upon light mi- – Interpretation: of about 20% for each five years of croscopic appearance, clinical be- ● Use of oral contraceptives confers use. havior, and epidemiology [325]. long-term protection against ovar- ● Protective effect in past users: ● Type I endometrial cancers, ian cancer. After cessation of the OC intake which have endometrioid histol- ● These findings suggest that oral the risk reduction for ovarian can- ogy (adenocarcinoma), are associ- contraceptives have already pre- cer endured. For each five years of ated with chronic exposure to vented thousands of ovarian can- OC use the risk of developing estrogen unopposed by a proges- cers and deaths from this malig- ovarian cancer was reduced by tin, and are often preceded by pre- nancy. It can be assumed, that over 29% in the first 10 years after ces- malignant disease (endometrial the next few decades the number of sation. The risk reduction was still hyperplasia).

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● Type II endometrial cancers have weak progestin (25 mg of dimethi- – Risk reduction in current users: non-endometrioid histology, usu- sterone) was the OC with the trade More than 15 case-control studies and ally papillary serous or clear cell name: Oracon™ [276]. It was re- at least five large cohort studies dem- histology, and an aggressive clini- moved from the consumer market in onstrated a decrease of the risk of en- cal course. Hormonal risk factors the 1970s after an association with an dometrial cancer of about 50% asso- have not been identified, and there increased risk for endometrial cancer ciated with the ever-use of OC [96, is no identifiable premalignant had been detected [702]. In addition it 338, 404, 474]. The limited number phase. became obvious that unopposed post- of elderly women who had used OCs Most endometrial cancers are adeno- menopausal estrogen therapy in non– does not allow an accurate estimation carcinomas [294]. hysterectomized patients led to an of the protection afforded after long Incidence: endometrial cancer. Four studies (one periods. – US National Cancer Institute cohort study and three large case-con- – Risk reduction in past users: (SEER) [283]: From 2003–2007, the trol studies) reported an increased Duration of use and protection median age at diagnosis for cancer of risk of endometrial cancer under after COC withdrawal: Longer du- the corpus and uterus was 62 years of estrogen replacement therapy [139, ration of use is associated with an in- age. There was no diagnoses under age 512, 593]. Three of these studies re- creased protective effect. This protec- 20; 1.6% of patients were diagnosed ported strong positive associations tive effect seems to persist for up to 20 between 20 and 34; 6.2% between 35 between estrogen replacement therapy years after stopping of OC use. and 44; 19.2% between 45 and 54; and risk of endometrial cancer with 30.9% between 55 and 64; 22.2% be- increased length of estrogen use. See Selected studies: tween 65 and 74; 15.0% between 75 also IACR report (1999) [338]. ● A reduced risk was also found as and 84; and 5.0% 85+ years of age. Combined oral contraceptives: For a function of longer COC use – The age-adjusted incidence rate was endometrial cancer, the absolute risk (> 5 years) in a case-control study 23.5 per 100,000 women per year. reduction by OC intake is smaller and from Washington State [695]. These rates are based on cases diag- more uncertain than for ovarian can- ● In a multicentric US study the OR nosed in 2003–2007 from 17 SEER cer. The estimated reduced risk of was 0.3 for 15–19 years and 0.8 for geographic areas. endometrial cancer in OC users may ≥ 20 years since stopping OC use – Germany: The local incidence of en- correspond to 1.000–3.000 deaths per [338, 402]. dometrial carcinoma is 24–25 cases year avoided in Europe [649]. ● In a Swiss study [417] the RR of per 100,000 women years, the mean The first reports about association of endometrial carcinoma was 0.4 for age of occurrence is 68 years at time endometrial cancer and oral contra- 10–19 years after stopping use, of diagnosis; 75% of patients are ceptives by [433, 434, 596], showed and 0.8 for ≥ 20 years. postmenopausal. Only 5% of all wo- an increased incidence of endometrial ● In a Swedish population-based na- men are diagnosed below age 40 cancer in users of a sequential oral tional case–control study the RR years [266]. contraceptive in the US (Oracon). The was 0.2 for ≥ 10 years of use, and – Mortality: The overall mortality of first studies demonstrating a decrease the subsequent use of hormone re- endometrial cancer is low. The annual of endometrial cancer incidence were placement therapy did not modify age adjusted cancer death rates of car- published by Horwitz & Feinstein the long-term protective effect of cinoma of the uterus (including cer- (1979) [264], Kaufman et al., (1980) previous OC use [700]. vix and endometrium) is estimated at [364]. about 4/100,000 [349]. Meta-Analysis: A meta-analysis by the – Progestin dosage: COCs with higher Risk factors [671]: IACR (1999) [338] included three co- progestin potency seem to be more – Increased risks for endometrial can- hort and 16 case-control studies, which effective for risk reduction of endo- cer are elevated steroid hormone lev- addressed the relationship between use metrial cancer [474]. els, estrogen therapy, high total of combined oral contraceptives and the – Low dose formulations with new number of menstrual cycles, obesity, risk of endometrial cancer. These studies progestins: Few data are available on , ovarian tumors, poly- consistently show: the more recent, low-dose formula- cystic ovarian syndrome, increasing – The risk reduction associated with tions. age, high caloric intake, diabetes, OC use for endometrial cancer, esti- – OC regimen: The beneficial effect family history, breast or ovarian can- mated at about 50%. seems to be independent of the com- cer, prior pelvic radiation therapy, en- – Duration of use and persistence: position of COC, i.e. dosage and type dometrial hyperplasia. The reduction in risk is generally of progestin, combined with EE 30– – Decreased risks are higher number stronger the longer the oral contra- 50 µg/day [474]. of pregnancies, use of an intrauterine ceptives are used and persists for at – Cautions: COC, POPs as well as device. least 10 years after cessation of use. LNG-IUS use effectively reduce en- Estrogens are potential Furthermore recent studies and re- dometrial hyperplasia, but should for the human endometrium: A se- views added additional information: only be used in exceptional cases in quential oral contraceptive with a – Cancer mortality: The RR of endo- patients with or after endometrial long unopposed estrogen phase (16 metrial cancer death was 0.2 in the 30 cancer [474]. tablets containing 100 µg of EE) fol- years follow-up of the Oxford-FPA – The mechanism for the risk reduction lowed by 5 days of 100 µg EE and a study [689]. of endometium cancer is still under

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discussion. Alternative contraceptive 30–50 µg/day [474]. Few data are tendency towards a relative risk be- methods to OC mechanisms to reduce available on the more recent, low- low control was found in nine studies, endometrium cancer are also un- dose formulations with new proges- a significant risk reduction was found known. tins. in two. – Copper-IUD (Metaanalysis by – Metaanalysis by Fernandez et al. Beining et al., 2008) [44]: Non-hor- Reviews and metaanalysis: 2001) [181]: This meta-analysis con- monal IUD use may be associated – IACR Monographs on the Evalua- sidered epidemiological studies on with a decreased risk of endometrial tion of Carcinogenic Risks to Hu- colorectal cancer published as full pa- cancer; however, the exact mecha- mans (2009) [278] pers in English up to June 2000, in- nism for this association is unclear. – Extended reviews: Grimes & cluding quantitative information on – IUD/LNG-IUS: Clinical studies are Ecomony (1995) [217] OC use. necessary to clarify the risk [474]. Cibula et al. (2010) [96], Mueck et al. ● Risk reduction in current users: (2010) [474] The pooled RR of colorectal can- Summary: cer for OC ever use from 8 case– Histology: Further references: control studies was 0.81, the Endometrial cancers are classified – The ESHRE Capri Workshop pooled estimate from 4 cohort into two major histological entities, Group (2005) [649]. studies was 0.84, and that from all also based on clinical behavior and – National Cancer Institute (US) studies combined was 0.82. epidemiology [325]. [294]. ● Duration of use: Duration of use ● Type I endometrial cancers (ad- was, however, not associated with enocarcinoma) account for 70 to 2.3.2.13. Cancer of Colon and Rectum risk, since the overall RR of colo- 80% of newly diagnosed cases of Disease: Cancer of the colon and rec- rectal cancer was 0.78 for short endometrial cancer in the United tum. duration of use and 0.85 for long States. They are associated with Histology: duration. The pattern of risk was chronic exposure to estrogen un- – Tumor histology will categorize the similar for colon and rectal cancer. opposed by a progestin, and are of- cancer into a particular type: (95% of ● Risk reduction in past users: The ten preceded by premalignant dis- all colon cancers), epidermoid carci- RR was 0.8 for ever OC use in a re- ease (endometrial hyperplasia). nomas (0.52–0.29 %) or other rare cent Swiss case-control study ● Type II endometrial cancers have types of cancer. [419]. Only two studies [49, 182] nonendometrioid histology. – The overall incidence of adenocarci- included information on recency noma increases with age until after of use. The results indicate that the Incidence: The absolute numbers of age 59, whereas epidermoid carci- risk reduction was stronger for new cases and deaths from endometrial noma, which is rare, occurs in indi- women who had used OCs more (uterine corpus) cancer in the United viduals aged 30–49. recently. States in 2010 are for new cases: 43,470 ● Risk and type of OCs: Little in- and for deaths: 7,950 [294]. Incidence: The contemporary incidence formation was available on the of colorectal carcinoma in US is pub- type of OCs, furthermore no het- Combined oral contraceptives: lished regularly by the SEER group erogeneous or systematic pattern – A historical sequential oral contra- [282]. The latest incidence rates for of trends of use was observed. ceptive with a prolonged estrogen colorectal carcinoma in women are 41/ ● Open questions: A better under- phase and a weak progestin (Oracon) 100,000 (US). standing of any potential relation caused endometrial cancer: The OC between OC use and colorectal was withdrawn from the market in the Combined oral contraceptives: cancer may help to make an in- early 1970s. – Risk reduction: OCs may also re- formed choice of contraception – At the level of the endometrium un- duce colorectal cancer risk. In fact, a [338, 402]. Some aspects, how- opposed estrogens might be carcino- role of hormonal factors in colorectal ever, remain undefined, including genic, lead to an endometrial hyper- carcinogenesis has long been sug- the risk profile in terms of duration plasia, and finally to endometrial can- gested, starting from the observation and recency of use and a more ad- cer. of an excess of colorectal cancer in equate control for confounding Current users: 15 case-controlled trials nuns [193]. A favorable role of hor- factors. It is therefore not possible and 5 cohort studies showed a risk re- mone replacement therapy in risk re- to provide any estimate of the po- duction of endometrial cancer resulting duction of colorectal carcinoma has tential impact of OC on colorectal from the use of COC of about 50%. been suggested [338, 402]. cancer incidence and mortality on – Clinical studies: Several studies have a population level. – Past users: The reduced risk of en- provided information on OC use and Summary: dometrial cancer seems to persist for the risk of colorectal cancer. The Incidence: The latest incidence rates for at least 15–20 years after stopping use. IARC (1999) [338] reviewed four co- colorectal carcinoma in the US for – Composition: The beneficial effect hort studies, three of which showed women are 41/100,000 [282]. seems to be independent of the com- risk reduction for ever OC use. 11 Combined oral contraceptives: position of COC, i.e. dosage and case-control studies did not show sig- – Risk reduction in current users: type of progestin, combined with EE nificantly elevated risks. Whereas a The pooled RR of colorectal cancer

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for OC ever use from 8 case-control See also Review Sabatini et al. (2011) ■ Increased SHBG leads to a de- studies was 0.81, the pooled estimate in this Supplement. crease in free testosterone from 4 cohort studies was 0.84, and Reduction of substance-specific side ■ 3rd generation progestins com- that from all studies combined was effects of modern combined oral con- pete less for binding with 0.82 [181]. traceptives [314]: SHBG – Duration of use: Duration of use Changes in dosage, substances and regi- ■ Some progestins (e.g. norgesti- was, however, not associated with mens of combined oral contraceptives mate) inhibitis 5α-reductase, risk, since the overall RR of colorec- influence the clinical side effect profile. leading to decreased DHT for- tal cancer was 0.78 for short duration A. Estrogen-related side effects mation. Formation of DHT is of use and 0.85 for long duration. The – Bloating, headache, nausea, mastal- necessary for any cellular ef- pattern of risk was similar for colon gia, leukorrhea, hypertension, melas- fects on skin/hair follicles and rectal cancer. ma/telangiectasia [351]. – Progestins, regimens and dosages: – Can be decreased by use of 20 µg EE ● COC with special anti-androgenic No data are available for low dose for- pills [554], which still have good progestins (cyproterone acetate, mulations and various regimens in- contraceptive efficacy or estrogen- chlormadinone acetate, dienogest, cluding use of modern progestins. free contraceptives with ovulation drospirenone, norgestimate) are Reviews and metaanalysis: inhibition (i.e. desogestrel contain- more effective in the treatment of – IACR-Monography (2009) [277] ing POP) acne and . – Extended reviews: Cibula et al. B. Progestin-related side effects Norgestimate and drospirenone (2010) [96] – Emotional instability, cyclic mastal- have only been approved for the Further references: gia, , fatigue, decreased li- treatment of acne in the US. – The ESHRE Capri Workshop bido, weight gain Group (2005) [649]. – These side effects tend to decrease 2.4.2. Severe Adverse Events with continued use In the following the review will focus on 2.4. Adverse Events and Health – Can be decreased by reducing the cardiovascular risk and cancer as severe Risks amount of progestin, increasing the adverse events listed in modern OC in 2.4.1. Mild and Moderate Adverse Events amount of estrogen per pill, changing patient information leaflets [279] in the Adverse events occurring in current us- the route of administration (patch, section warnings and precautions: ers of combined oral contraceptives in- vaginal ring) or using the “long- – Thrombotic and other vascular events clude the following categories: severity cycle” as an “off-label” recommen- – Carcinoma of the breasts and repro- by symptoms and targets, adverse events dation ductive organs leading to discontinuation of COC use Androgenic side effects – disease and common OC related, treatment- ● Third generation progestins such – High blood pressure emergent, adverse reactions. as desogestrel, and also norgesti- – and lipid metabolic ef- Adverse reactions leading to COC dis- mate (a more recent 2nd generation fects continuation: progestin) were developed and – Headache – Number of women discontinued from marketed as “less androgenic” pro- See also Review Sabatini et al. (2011) the clinical trials due to an adverse re- gestins than older preparations in the Part 2 of this Supplement. action. ● In fact, studies of androgenicity of 2.4.2.1. Metabolic Effects of Oral Con- – The most frequent adverse reactions progestins are based on rat models, traceptives leading to discontinuation were i.e. the binding of steroids to rat Between 1970 and 1990 one main target metrorrhagia and irregular menstrua- ventral prostate [113]. These artifi- in the development of new oral contra- tion, acne, headache,migraine and cial rankings did not take into ac- ceptives was a low or no impact on se- weight increase. count dose adjustments or the dif- rum lipids, and hemosta- ferential effect of steroid hor- sis in order to protect vascular health and Common treatment-emergent adverse mones on different target tissues in prevent cardiovascular events. reactions (> 2%): humans. Hence they are not clearly – New progestins, low-dose formula- – Headache (including migraine) clinically fundamental [621, 657]. tions and regimens of OC were devel- – Metrorrhagia and irregular menstrua- Anti-androgenic effects oped with the intention to provide tion ● All combination OCs are mildly oral contraceptives with as little meta- – Breast pain, discomfort or tenderness anti-androgenic: OCs inhibit LH bolic impact as possible. – Nausea or vomiting and thus decrease ovarian produc- – No changes in metabolism are gener- – Acne tion of testosterone; estrogen leads ally considered beneficial, whereas – Increased weight. to increased sex hormone binding positive or negative changes must be Mild to moderate adverse events: globulin (SHBG) production by individually proven to be beneficial – Bleeding irregularities the liver, progestin decreases or harmful. Changes of selective pa- – Emotional disorders SHBG. The overall effect of OCs is rameters must be seen in a metabolic – Gallbladder disease an increase of SHBG. balance of the whole functional sys- – Interference with laboratory tests ■ 3rd generation progestins in- tem (i.e. hemostasis). – Drug interactions crease SHBG more than mono- – The extrapolation from changes of – Other conditions. phasic older preparations [620]. laboratory parameters to clinical rel-

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evance is difficult and delusive – es- – Current guidelines indicate that, simi- – Progestin-only pills and injectable pecially concerning lipid metabolism lar to general , contracep- progestin have only minor effects on and hemostasis. tive hormones should be selected and plasma lipoproteins [132]. – In general all new COC products cur- prescribed on the basis of individual Combined OC: rently on the market show only a risks and benefits. – Wingrave (1982) [715] described a small metabolic impact and are con- – Women seeking advice for oral con- correlation between serum lipids and sidered as safe. traception especially at the age of 35 progestin dose in older high dose Different clinical effects of various years and older should be assessed for combined oral contraceptives in a progestins on the risk for venous cardiovascular risk factors including study investigating three brands of thromboembolism have been found hypertension, smoking, diabetes, ne- OC. The depression of HDL-choles- but the underlying mechanisms are phropathy, and other vascular dis- terol was strongly associated with the still under discussion. eases, including migraine, prior to progestin dose. The effect of long-term OC use on the use. – The net effect depends on the balance prevention of cardiovascular events is – The existing data for OC and cardio- between estrogen and progestin doses crucial. Cardiovascular risk factors like vascular risk have to be carefully and the amount and activity of the elevated lipids, carbohydrates and blood evaluated for the possible risk but also progestin. pressure, as well as exposure to exog- protection from atherosclerosis and – Changes in serum triglyceride levels enous noxious factors such as cigarette cardiovascular events. Long-term car- have been reported with combined smoking, nutrition, alcohol and drugs diovascular follow-up of women with OC use [311]. are important. Protective factors such as prior OC use, including subgroup in- – Individual progestins have specific physical activity and lifestyle modifica- formation concerning ovulation, pharmacological profiles and these tions should also be considered. hyperandrogenism, weight, lipid und findings cannot be extrapolated to all Today more specific molecular aspects glucose metabolism, e.g. insulin re- progestins. For example, use of COCs of cardiovascular risks are shifting into sistance and the presence of pro- with desogestrel and drospirenone the focus of research and prevention. thrombotic genetic disorders is leads to an increase of HDL and a de- According to a review by Moreno et al. needed to address this important is- crease of LDL [426]. (2009) [470] vascular health can be sue. – Among the progestins used in OCs, achieved by reducing vessel wall injury In the following, the known effects of the progesterone derivatives possess and promoting physiological repair. Ves- estrogens and progestins as well as com- no or only weak androgenic and sel wall homeostasis requires a precise binations of both in the form of com- partly anti-androgenic properties, balance between injury and the defense bined oral contraceptives on lipids, car- whereas the nortestosterone deriva- mechanisms of repair. To promote vas- bohydrates and hemostasis are described tives generally have a more or less cular health, the destruction of the vessel in detail. pronounced androgenic potency. wall should be reduced, whereas physi- Therefore, the combination of EE ological mechanisms leading to a resto- 2.4.2.1.1. Lipid Metabolism with higher doses of LNG may cause ration of vessel wall function should be Changes in lipid metabolism might be an increase in LDL- and a enhanced. Three main defense mecha- causal for development of atheroscle- decrease in HDL-cholesterol 132, nisms are responsible for maintaining rosis and cardiovascular disease. 384, 425]. cardiovascular homeostasis: Lipid metabolism may be affected by – In contrast, when using triphasic OCs ● regenerative production of en- sexual steroids in a dose- and time- with low-dose LNG, the effect on the dothelial progenitor cells, dependent manner [383, 452, 474]. lipid metabolism does not appear to ● vessel wall angiogenesis, be unfavorable [52, 203, 452, 672]. ● macrophage-mediated reverse Estrogens: – Current users: 1966, the Swedish cholesterol transport. – In general, treatment with potent group of Aurell et al. (1966) [31] estrogens increases the plasma con- published their findings on eight Summary of cardiovascular effects of centrations of triglycerides and the women treated with Anovlar (50 µg COC from the point of view of a cardi- components of HDL and decreases EE plus 4 mg norethindrone) for 1 ologist (according to Shufelt et al. those of LDL [575]. year. These authors demonstrated in- 2009) [595]: Progestins: creased serum levels of total choles- – A variety of basic science, animal, – Decreasing HDL cholesterol levels terol (25%, p < 0.001), phospholipids and human data suggests that contra- have been reported for many pro- (27%, p < 0.001), and “glycerides” ceptive hormones have antiatheroma- gestins, especially those with andro- (mostly triglycerides), the latter in- tous effects; however, less is known genic activity. Less androgenic pro- creasing 64% from 0.70 to 1.15 mmol/ regarding the impact on atherosclero- gestins (i.e. ethinodiol diacetate) af- L (70 to 102 mg/dL; p < 0.01). HDL sis, thrombosis, vasomotion and fect the lipid metabolism to a lower cholesterol levels fell 24% from 1.6 arrhythmogenesis. degree than norgestrel or norethin- to 1.2 mmol/L (60 to 46 mg/dL; – Newer generation OC formulations drone [211, 385, 732]. p < 0.001). indicate no increased myocardial inf- – Androgens and progestins with an- Time-dependent changes: In general, arction risk for current users, but a drogenic activity counteract the changes in the lipid metabolism are persistently increased risk of venous estrogen-dependent effects to a cer- fully expressed within 3 months of thromboembolism. tain extent. OC use, do not progress with contin-

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ued exposure, and are fully reversible by Rabe and coworkers: studies on special restrictions and safety recom- after cessation of treatment [186]. monophasic OCs with gestodene mendations have to be taken into ac- – Past users: In general, lipid changes [534], monophasic OCs with nor- count. are fully reversible when therapy gestimate [537], monophasic OCs ceases [186]. with levonorgestrel and gestodene 2.4.2.1.2. – Dosage: [537] were conducted. The increasing incidence of type 2 dia- The first detailed evaluation of the – See also the review by Rabe et al. betes worldwide is a well-known fact. metabolic effects of OC came from (1988) [535] analyzing the impact of Considering hormonal contraception it the UK in 1966. Wynn et al. (1966) various monophasic and triphasic is important to stress the association be- [731] compared serum lipid and lipo- oral contraceptives on serum lipids. tween combination oral contraceptives protein levels in 102 women taking – No Cochrane analysis available. (OCs) and glucose intolerance. Prospec- various OC formulations (> 80% con- tive cohort studies of both high-dose taining 100 µg mestranol plus 0.5-2.0 Summary: estrogen-progestin formulations [546] mg ethynodiol diacetate) with those Cardiovascular disease and lipids: and modern low-dose estrogen-proges- in 75 women not using OC. The re- – Changes in lipid metabolism might tin formulations [90] did not find an in- sults for the individual lipids are cause atherosclerosis and cardiovas- creased incidence of type 2 diabetes in listed below: cular disease (CVD). New informa- current OC users or former OC users. – Cholesterol: tion collected from epidemiological However, the study populations had Lowering of the estrogen dose to and interventional studies with lipid higher age at enrolment and were not 50 µg without altering the progestin blockers led to new perspectives on adjusted for race. Fasting glucose or in- content of the OC resulted in less pro- the best predictive lipid markers for sulin levels were not documented as pa- nounced hypertriglyceridemia and no CVD, initially cholesterol, later on rameters for the effect of OCs on glucose change in serum cholesterol levels triglycerides, finally lipoproteins and insulin metabolism. [733]. LDL, and a combination of the others – Triglycerides: were discussed. The epidemic increase in the incidence For older high dose COC, fasting se- Steroidal effect: of diabetes and impaired glucose toler- rum triglyceride levels were 70% to – It is presumed that the lipid metabo- ance is one of the leading causes of 80% higher in OC users than in non- lism is affected by sexual steroids in a morbidity and mortality worldwide. In users (p < 0.001), with one-third of dose- and time-dependent manner both disorders, tissues such as muscle, these women having values exceed- [383, 390, 452]. fat and liver become less responsive or ing the highest level of any non-user Combined oral contraceptives: resistant to insulin. Obesity, polycystic Wynn et al. (1966) 731]. – Estrogens lead to hypertriglyceri- ovarian disease, hyperlipidemia, hyper- – Hypertriglyceridemia is an estrogen- demia in a dose-dependent manner. tension and atherosclerosis are linked dose-dependent effect mediated by – Progestins with androgenic activity with insulin resistance and diabetes. stimulation of both lipogenesis [442] (i.e. levonorgestrel) have a stronger The pathophysiology of insulin resist- and the synthesis of the apoprotein of negative impact on lipid metabolism ance involves a complex network of very-low-density lipoprotein [28]. than non-androgenic or antiandroge- signaling pathways, activated by the in- nic progestins (i.e. progesterone de- sulin receptor, which regulates interme- – Lipoproteins HDL and LDL: rivatives). diary metabolism and its organization – High dose norethindrone formula- – In OC users, the following changes in in cells [573]. tions can increase LDL levels and re- serum lipids as a proportion of base- duce those of HDL [425]. Reducing line values before OC use were ob- In the Walnut Creek cohort the high the progestin dose minimizes these served comparing monophasic to prevalence of OC users with impaired changes; the increase of HDL levels triphasic preparations [535]: glucose metabolism contrasts with the was shown for 500 µg norethindrone – cholesterol: ± 12 % low incidence of diabetes mellitus [73, 207]. – triglycerides: –10 % to + 50 % found for the entire population. After – Higher dosed levonorgestrel-contain- – HDL- 10 years of follow–up, only 25 cases of ing OCs increase fasting LDL levels cholesterol: –13 % to + 24 % diabetes mellitus had been documented and reduce those of HDL. – LDL- among 16,638 women. However, after – Reducing the levonorgestrel dose re- cholesterol: –22 % to + 15 % an average of 8.5 years of follow-up, sulted in less effect on LDL and HDL Modern low dose combined oral contra- the mean age of women who had ever – to the extent that triphasic levonor- ceptives cause only mild changes of se- used OCs was less than 40, too young gestrel formulations have relatively rum lipids. Nevertheless, monitoring of for the study of the risk of adult-onset little effect on either lipoprotein. serum lipids in healthy women using diabetes [511]. – Progestins with androgenic profile COC is recommended in special circum- led to a more pronounced effect of stances. Kim et al. (2002) [373] analyzed cross- lowering HDL-cholesterol. sectional associations in women (n = In women with (pre-) pathological lipids 1,940) in the Coronary Artery Risk De- Regimens: and obese women especially with ad- velopment in Young Adults (CARDIA) – Different formulations and regimens ditional risk factors (i.e. age, smoking, study, a prospective observational study of OC have been intensively studied hypertension, diabetes thrombophilia) of African-Americans and whites aged

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18–30 years at enrolment in 1985–1986 Progestins: traceptives slightly increased the fast- in view of OC use, fasting glucose, insu- – Progesterone has little effect on car- ing glucose levels, serum glucose lev- lin and the presence of diabetes. Current bohydrate tolerance compared to syn- els and serum insulin after an oral glu- use of OCs was found to be associated thetic progestins [360]. cose load. After cessation of COC this with lower glucose levels in young Afri- – Progestins inhibit the uptake of glu- effect was reversible. can-American and white women and cose in the muscle tissue and in fat – The modern combined oral contra- probably associated with lower odds of cells by a reduction of the action of ceptives with low estrogen content diabetes. insulin. In the liver, however, proge- (20 µg EE) containing gestodene or stins promote the storage of glyco- desogestrel cause only a slight in- The regulation of the glucose metabo- gen. crease in fasting blood glucose levels lism in the liver is summarized by Saltiel – The effect of progestins on the im- compared to higher doses of estrogen and Kahn (2001) [573]. pairment of the carbohydrate metabo- and progestins such as levonorgestrel Estrogens and progestins can change lism depends on the androgenicity of (RCT with n = 36) [741]. fasting serum glucose, insulin and insu- the compound and the dosage of the – Combined OCs may decrease glucose lin resistance. OC as could be shown in the Walnut tolerance in some users, but appear to Creek cohort study [511]. have no effect on fasting plasma glu- Estrogens: – For 3 commonly used and structurally cose in non-diabetics [311]. – Estradiol, , and estrone may similar progestins (norethindrone, – Since estrogens administered alone improve glucose tolerance in nondia- norethindrone acetate, and ethyno- do not alter glucose tolerance, the dia- betic women and reduce insulin re- diol diacetate) regression slopes indi- betogenic effect may be mainly due to quirements in diabetics [360]. cated a 5–10 mg% increase in serum the progestin. Estrogen may play a – Estrogens seem to have little effect on glucose per milligram of progestin role in inhibiting the catabolism of the insulin resistance in muscle and adi- exposure, both for 1- and 2-hr test re- progestin [486], thereby potentiating pose tissue. Kalkhoff (1972) [360] sults. its effects [733]. could demonstrate no effect on glu- – For two other progestins, norethyno- Regimen: Different formulations and cose tolerance in women using oral drel and , no relation- regimens have been intensively stud- contraceptives and non-contraceptive ship between milligrams of exposure ied by Spellacy et al.: Triphasic with userexamined as controls after ad- and serum glucose level is assumed. norethindrone [613] triphasic with ministration of mestranol (80 µg/day) – For the structurally unique compound levonorgestrel [617]; triphasic with and EE (50 and 500 µg/day). norgestrel, the regression slopes re- norethindrone [613]; as well as Rabe – COC containing an estrogen dose of flected an 18–35 mg% increase per and coworkers: monophasic with ge- ≥ 75 µg combined with an milligram. stodene [534], monophasic with nor- progestin caused the greatest deterio- – It can be anticipated that users of gestimate [537], monophasic with ration in glucose tolerance associated norgestrel-containing pills show the levonorgestrel and gestodene [537], with impaired insulin secretion, greatest decrease in glucose tolerance triphasic with norethindrone [536]. hypercholesterolemia, and hypertri- because OCs contain norgestrel at the glyceridemia. Lowering of the oestro- same or slightly lower doses than Summary: gen dose to 50 µg without altering the norethindrone. A deterioration of the carbohydrate me- progestagen content of the COC re- – Ethynodiol diacetate, a weak andro- tabolism through OC use is found in dia- sulted in less deterioration of glucose genic progestin, showed a lesser ef- betic women. New progestins, low dose tolerance, increased insulin secretion, fect on glucose tolerance than nor- formulations and regimens were in- less pronounced hyper-triglycerid- gestrel [511]. tended to develop products with as little emia, and no change in serum-choles- – Norethynodrel did not affect glucose metabolic impact as possible. terol level [734]. These results indi- tolerance [511]. Estrogens: Estrogens alone seem to cate that the estrogen content of OCs – In general, strongly androgenic pro- have little effect on insulin resistance in should be reduced as far as is practical gestins seem to have the greatest ca- muscle and . in order to reduce the diabetogenic pacity to adversely affect the metabo- Kalkhoff et al. (1972) [360] could dem- and hypertriglyceridemia effects. The lism while estrogenic progestins have onstrate no effect of mestranol (80 µg/ metabolic impact of estrogens on the the least adverse metabolic impact day) and EE (50 and 500 µg/day) on glu- carbohydrate metabolism might be [511]. cose tolerance in women using oral con- different if estrogens are applied – Different progestins have been inten- traceptives and non-contraceptive users alone or in combination with proges- sively studied by Spellacy et al., i.e. examined as controls. tins as well as if they are applied in norethindrone [615], norgestrel [612], A reduction of the estrogen dosage in continuity instead of in an intermit- ethynodiol diacetate [614], gestodene combined oral contraceptives leads to a tent or acute application mode; see [616] as well as Rabe et al.: gestodene lower impact on the carbohydrate me- data of described above [360]. and levonorgestrel [538], norgesti- tabolism. – With the gonane-containing COC mate [537], norethisterone [536]. whose estrogen content was reduced Progestins inhibit the uptake of glucose from 50 to 30 µg EE, glucose intoler- Combined OC: in muscle tissue and in fat cells by a re- ance and hypertriglyceridemia were – Numerous earlier studies found that duction in insulin action. This effect is reduced [733]. older higher-dose combined oral con- dose-dependent: The increase in dosage

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 85 Oral Contraceptive Pills of 1 mg leads In a 6-month, randomized, double- – An unfavorable effect of the progestin to an increase (by about 10 mg/dl) in the blind study the effects of two com- component might prevent a further 1- and 2-hour values in the oral glucose bined oral contraceptives containing reduction of the risk for VTEs when tolerance test [511]. 150 µg desogestrel and either 20 or using OCs with 20 µg EE [711]. 30 µg EE on hemostatic parameters – Although single progestins have no or Combined oral contraceptives were investigated in 1633 healthy only minor effects on hemostasis, – According to Kim et al. (2002) [373] women. A less pronounced effect on they can modify the action of EE on most studies with combined progestin/ hemostasis was found with the 20 µg certain coagulation and fibrinolysis estrogen contraceptives indicate that EE preparation compared to the 30 µg parameters, depending on their an- OCs are associated with increased glu- EE formulation, both in combination drogenic activity [391, 571, 717]. cose and insulin levels [207, 208, 630, with the same dosage of desogestrel – In a comparative trial the effects of 361]. However, the postulated associa- (150 µg) [716]. EE dose (50, 30 and 20 µg) and pro- tion is not consistent throughout the In the Oral Contraceptive and gestin type (desogestrel, gestodene, studies. This inconsistency may be ex- Hemostasis Study Group (2003) levonorgestrel and norgestimate) in plained by the small number of partici- [652], 24 hemostatic parameters were oral contraceptives were investigated pants and the inability to evaluate and analyzed over 6 cycles in women tak- in 707 healthy women for 6 cycles adjust for all potential confounders, ing OCs with an EE dose of 50, 30 and 24 hemostatic parameters were such as increased BMI, age, nonwhite and 20 µg in combination with differ- measured [652]. race, lower education level, family his- ent progestin types (desogestrel, ge- ● Significantly greater increases in tory of diabetes, or health behaviors. In stodene, levonorgestrel and norg- prothrombin fragment 1+2 and addition, selection bias may play a estimate). The estradiol dose (50 vs factor VII (activity and antigen) role; in particular, studies without a 30 µg) significantly influenced these were found in the DSG, NGM and correlation between diabetes and OCs hemostatic parameters. No consistent GSD groups compared to the LNG did not exclude women with diabetes, EE effect was detected except for the group. on the other hand women with diabe- ETP-based APC-sr and soluble fibrin, ● Similarly, significantly lower lev- tes were treated with OCs less often which increased to a higher degree in els of protein S (free and total) and because of their risk profile [127, 520]. the 50 µg EE dose group. increased APC-sr (endogenous All low dose combined oral contracep- – Estradiol: Differences between EE thrombin potential based) were tives currently on the market show only a and estradiol on hemostasis. found in the same groups com- slight impact on carbohydrate metabo- Although only few data exist compar- pared with the LNG group. lism in healthy women. ing EE vs. E2 without the addition of ● In addition, the estradiol dose In prediabetic and diabetic women spe- a progestogen, it seems plausible (ba- (50 vs 30 µg) significantly influ- cial restrictions and safety recommenda- sed on known effects for various he- enced these parameters. No con- tions must be considered especially if patic proteins) that all hepatic effects sistent EE effect could be dis- additional risk factors (i.e. age, smoking, in terms of hemostatic factors are cerned except for the ETP based obesity, hypertension, thrombophilia) much stronger using EE. For exam- APC-sr and soluble fibrin, which are present. ple, in a cross-over study, the effect of increased more in the 50 µg EE 10 µg EE vs 2 mg E2val per day was dose group. 2.4.2.1.3. Hemostasis tested during treatment of 24 post- ● All changes were within the nor- Hemostasis is a complex physiological menopausal women for six weeks, mal range and have not been asso- process involving three mechanisms to leading to a significant and much ciated with an increased risk of a stop the blood flow: vasoconstriction, stronger increase of various he- venous thromboembolic event. platelet formation and clotting of blood. mostasic parameters during the use of ● However, raised levels of these Intact blood vessels are central to moder- EE [424]. Although fibrinolytic fac- variables are associated with a ating the tendency of blood to clot. The tors may also be increased, on the prothrombotic risk situation such integrity of endothelial cells prevents whole, with EE a higher increase in as pregnancy. thrombus formation by secreting tissue coagulation compared to fibrinolysis ● The significance of the hemostatic plasminogen activator and inactivating with a higher risk of a venous throm- changes found in this study in rela- thrombin and adenosine diphosphate. boembolic event (VTE) must be ex- tion to VTE risk remains to be de- Injury to vessels overwhelms these pro- pected, even if lower dosages of EE fined. The results of this study can- tective mechanisms and the coagulation (10 µg) than in COCs (20–50 µg) are not explain the differences in risk cascade is activated. used compared to the dosages of E2V of VTE between OCs containing Steroid hormones may influence all (2.000 µg), which are now used in the different progestins. three mechanisms. In the following part first COCs with E2val or E2, respec- – Oral contraceptives reduce the APC of the paper the main focus will be on the tively, instead of EE. sensitivity of the APT time (by about effects of contraceptive steroids and 10%) as well as the plasma concentra- blood coagulation as well as fibrinolysis. Progestins: tion and activity of antithrombin (by – Progestins have differential effects on about 10%) and protein S (by about Estrogens: the intrinsic and extrinsic proco- 20%) [45, 246, 377, 440]. – Ethinyl estradiol: The net effect on agulant activity [249, 376, 391, 563, The effect appears to be more pro- hemostasis depends on dosage of EE. 571, 717]. nounced with high dose (50 µg of EE)

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OC, whereas no differential impact of sis parameters depending on their an- sexes with age [140, 141, 172, 245] progestins has been described [717]. drogenic activity can be modified in and VTE in a young, healthy woman – Oral contraceptive use is associated combination contraceptives [391, is very rare. According to Heit et al. with reduced anticoagulant capacity 571, 717]. (2001) [244] hospitalized patients in the presence of increased coagula- – The changes in hemostasis param- have a 100 times higher risk than non- tion activity and increased plasma eters observed during clinical studies hospitalized patients for VTE. One in concentrations of some coagulation cannot sufficiently explain the asso- ten patients dying in hospital or 1 per- factors. An association of these chan- ciation between OC use and increased cent of all patients admitted die due to ges with the risk of VTE has not yet risk of VTEs. pulmonary embolism [485]. been firmly established [717]. – Inherited disorders of blood coagula- – The changes in hemostasis param- tion determine the increased risk of Regional differences: Although it is a eters observed during clinical studies VTE in OC users: i.e. factor-V Lei- well known fact that cardiovascular cannot explain the association be- den, prothrombin polymorphism, an- disease is the predominant cause of tween OC use and increased risk of tithrombin, protein C and protein S. mortality among women worldwide, VTEs. In patients with risk factors, All low-dose combined oral contracep- the proportion of 80% of all cardio- i.e. deficiencies of coagulation inhibi- tives currently on the market show only a vascular deaths in women occuring in tors or resistance to activated protein slight impact on blood coagulation. developing countries is underesti- C, OCs may enhance a preexisting Nevertheless in cases with a positive mated. In , cardiovascular dis- imbalance in the control of coagula- family history of cardiovascular disease, ease is the major killing factor of tion [679]. positive patient history of CVD, known women in both urban and rural set- – Such a predisposition might explain thrombophilia and additional risk fac- tings, surpassing female deaths from the observation that the risk is highest tors (i.e. age, smoking, obesity, hyper- cancer and respiratory disease [703]. in the first year of OC use [247]. tension, diabetes), special restrictions – Winkler (1998) [717] analyzed and safety recommendations must be Prevention: eighteen studies comparing second- considered. – Independent of sex, race, or income, and third-generation oral contracep- cardiovascular disease (CVD) is by tives on the basis of their effects on 2.4.2.2. Cardiovascular Risk far the leading cause of death in the hemostasis. Significant changes from Incidence: world, with an unsustainable eco- baseline were reported for many vari- – An estimated 17 million people die of nomic burden for societies. ables with both second- and third- CVDs, particularly heart attack and – The health systems need to be revised generation oral contraceptives with- stroke, every year [329]. to reduce cost and promote health. out significant between-group differ- – Many adults in the United States ex- This implies a major shift of mental- ences. In addition, in a combined hibit high risk factors for cardiovas- ity: from disease treatment to promo- analysis of non-significant changes, cular disease (CVD). Total blood cho- tion of health [470]. no consistent pattern of change lesterol levels exceed 200 mg/dl emerged for any marker with the ex- among more than 100 million adults; Key messages to protect heart health ception of higher factor VII levels as- approximately 70 million have diag- (according WHO, 2011) [328] sociated with third generation oral nosed or treated high blood pressure – Heart attacks and strokes are major, contraceptives. (systolic blood pressure 140 mmHg or but preventable killers worldwide. diastolic blood pressure 90 mmHg), – Over 80% of cardiovascular deaths Regimen: No meta-analysis or Coch- and over 50 million people still occur in low- and middle-income rane systematic review is available. smoke [327]. countries and almost equally in men Summary: – In the European Union each year and women. – Ethinyl estradiol: formulations with there are an estimated 1.1 million di- – The cardiovascular risk of women is less EE have lower impact on hemo- agnosed cases of venous thromboem- particularly high after the menopause. statis. bolism including deep vein thrombo- – Tobacco use, unhealthy diet, and – Estradiolvalerate and estradiol, resp., sis (DVT) and pulmonary embolism, physical inactivity increase the risk of are used in a recent modification of of which 150,000 are fatal [106]. heart attacks and strokes 2–3 fold. the first COCs instead of EE in dos- Most thromboembolisms are without Cessation of tobacco use reduces the ages of about 2 mg or 1.5 mg/day, symptoms and therefore not diag- risk of a heart attack or stroke. resp., which have a much lower im- nosed. Cohen et al. (2007) 106] esti- – Engaging in physical activity for at pact on hemostasis compared to dos- mate that approximately 220,000 least 30 minutes every day will help ages of EE used in COCs. deaths in Europe are due to undiag- to prevent heart attacks and strokes. – Progestins have differential effects nosed pulmonary embolism. Due to – Eating at least five servings of fruit on the intrinsic and extrinsic pro–co- this fatal complication and chronic and vegetables a day and limiting agulant activity [249, 376, 391, 571, sequelae the VTE is considered a seri- your salt intake to less than one tea- 717]. ous health problem. In the EU every spoon a day also helps to prevent – Although the exclusive use of year more people die from VTE than heart attacks and strokes. progestins has no or only minor ef- from breast cancer, HIV/AIDS and – High blood pressure has no symp- fects on hemostasis, the action of EE traffic accidents. However, the inci- toms but can cause a sudden stroke or on certain coagulation and fibrinoly- dence increases exponentially in both heart attack.

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– Diabetes increases the risk of heart at- 2.4.2.2.1. Cardiovascular Disease (CVD) Hannaford et al. (2010) [229] the tacks and stroke. and Combined Oral Contraceptives authors did not examine whether the – Being overweight increases the risk General considerations (according to risk of death varied with the hormonal of heart attacks and strokes. To main- Hannaford, 2000) [227]: content of the contraceptive pills tain an ideal body weight, regular Data base: Evidence on cardiovascular used. Most (75%) of the pills used in physical activity and a healthy diet is risk and the use of combined oral con- the study contained 50 µg of estrogen, necessary. traceptives is based on studies con- the remaining women used oral con- – Heart attacks and strokes can strike ducted against a background of low traceptives with more than 50 µg suddenly and be fatal if assistance is cardiovascular risk in young women, (12%), less than 50 µg formulations not sought immediately. changing COC composition and (10%), and progestin only prepara- Pathomechanism: changing user selection and monitor- tions (3%). Most women used prepa- – According to a review of Moreno ing [227]. rations from more than one estrogen et al. (2009) [470] atherosclerosis dose category, almost entirely in a evolves from subendothelial reten- – Number of subjects for clinical tri- step-down direction – for example, tion of lipoproteins through the als: The inability to recruit large from a > 50 µg preparation to a 50 µg leaky and defective endothelium, numbers of women exposed to any preparation. Lack of exclusive use of where these plasma molecules are particular formulation has caused epi- any particular dose category means modified (i.e., oxidized) and become demiologists to rely on less specific that any associations between death cytotoxic, proinflammatory, chemo- analyses when assessing the possible and estrogen dosage may be due to taxic, and proatherogenic. The re- influence of the hormonal content of the effects of the preparation used sponse-to-injury hypothesis consid- COCs on cardiovascular risk. most recently before death or linger- ers inflammation as a central mecha- – Estrogen content: The causal asso- ing effects from a previously used nism responsible for early athero- ciation between very high doses of (usually higher dose) formulation. genesis. estrogen and cardiovascular side ef- – Regimen: In recent years, a number – Arterial wall injury, mostly mediated fects – and in particular thromboem- of publications have suggested mate- by aging, diabetes, smoking, hyper- bolism – is well established (The rial differences in the cardiovascular cholesterolemia, and hypertension, Coronary Drug Project 1973) risk profiles of particular COC formu- triggers an inflammatory response, a [648]. In the past the impact of the lations. A World Health Organization defense mechanism to restore arterial estrogen component of COCs was of- (WHO) Scientific Group reviewed wall integrity. ten evaluated by breaking down the much of the evidence in November – However, persistence of risk factor- preparations into those containing 1997 [459, 725]. A more recent inter- mediated arterial wall injury leads to > 50 µg, 50 µg, < 50 µg of EE. Such national consensus paper on venous endothelial dysfunction, atheroma- categories ignore the pharmacologi- thromboembolism was published by tous plaque formation, plaque rup- cal effects of the accompanying pro- Reid et al. 2010 543]. ture, and thrombotic complications, gestin. Moreover, preparations con- – Bias: A number of explanations, in the overall process of atherothrom- taining lower doses of estrogen usu- terms of biological plausibility, as bosis. ally also have lower doses of proges- well as bias or confounding factor, – Simultaneously, inflammation also tin than those with a higher estrogen have been proposed for the rather orchestrates a process of repair content; in addition the progestin may small differences in cardiovascular through three main defense mecha- be different. These changes cannot be risk between COCs. Clinical evidence nisms: 1) endothelial repair by pro- compensated for by statistical adjust- for these explanations, however, is genitor cells, 2) plaque neovascula- ments. Analyses of so-called high- weak in most instances. rization, 3) reverse cholesterol trans- dose (≥ 50 µg) versus so-called low- Case-control studies: In case-control port. dose (< 50 µg) pills, therefore, are trials with diseases that are influenced only crude comparisons between by strong prognostic factors (such as Predictive parameters: older and more recently available age for cardiovascular disease) a – Clinical parameters: Many previous COCs. Comparisons between ‘low- matched case-control design should studies have suggested significant ef- dose’ preparations containing for ex- be considered. It is important that the fects of body weight, height, choles- ample 30 µg and 20 µg EE are often information on the outcome of inter- terol, heart rate, BMI, skinfold thick- more reliable as the progestin content est as well as the exposure is valid and ness, obesity, nutrition, smoking, oral of these preparations is often identi- precise. contraceptive use, menopausal status, cal. Although generally imprecise, Controls: OC never-users are nowa- stress and physical activity on blood such comparisons have been helpful days not available in large numbers pressure. when trying to assess whether the for clinical and epidemiological trials – Laboratory parameters: lipids (tri- overall risk of cardiovascular disease as controls (less than 5% of the total glycerides, LDL-cholesterol, HDL- associated with COC use has declined female population in Germany, have cholesterol), carbohydrates (fasting over time. never taken hormonal steroids – this glucose, fasting insulin, insulin resist- group may also have several other ance (HOMA-index), glucose load- In an evaluation assessing overall risk factors leading to the decision not ing, HbA1c) CRP, thrombophilia and mortality in a study at the Royal Col- to use combined oral contraceptives uremic acid. lege of Practitioners in 2010 by or any hormonal contraceptive).

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– Adjustment: for each known risk Changes in systolic pressure, car- NETA 12.3 cases/1000 WY; 4 mg factor with a clinically relevant im- diac output and stroke volume are NETA: 13.9 cases/1000 WY. pact on the outcome, the analysis consistently greater than in dia- Progestin-only OCs do not appear must be adjusted. If a new important stolic pressure. to increase blood pressure signifi- risk factor is detected, all other stud- ● Estrogens and their dose in relation cantly. A 2003 systematic review ies published without the risk factor to hypertension by Hussain (2004) [334] included are potentially biased and their con- Theoretically the effect of estro- four studies in normotensive wo- clusions may be invalid. gen as a protective factor on men treated with progestin-only – Risk reduction of CVD (practical the vascular system has been OCs, three prospective control tri- advice): The risk of cardiovascular stated; premenopausal and post- als and one cross-sectional survey. disease of any description is low in menopausal women differ as well The author reported no significant COC users. Women can minimize, as age-matched premenopausal association between high blood and possibly eliminate entirely, their women and men in blood pressure pressure and the use of progestin- arterial risks by not smoking and by [160]. only OCs over up to 2–3 years. having their blood pressure checked Higher doses of EE induce arterial However, individual progestins before using a COC (in order to avoid hypertension in about 5% (OC have specific pharmacological its use if raised blood pressure is dis- with at least 50 µg of EE), whereas profiles and these findings cannot covered). The most reliable way to OC with lower doses of EE only be extrapolated to all progestins. minimize the risk of venous throm- lead to a smaller increase of hyper- For example, drospirenone has boembolism is to restrict the prescrip- tension [91]. substantial antimineralocorticoid tion of COCs to women who have no ● In her review, Hussain (2004) activity and it was demonstrated in risk factor. [334] reported on three prospec- several randomized clinical trials tive control trials and one cross- that drospirenone/estrogen combi- 2.4.2.2.2 Arterial Disease sectional survey and found no sig- nations lead to a reduction of the 2.4.2.2.2.1 Hypertension nificant association between high systolic as well as diastolic blood Incidence: blood pressure and the use of pro- pressure [491, 527, 707]. In addi- – The incidence of arterial hypertension gestin only pills (POPs) for up to tion, the LASS study demonstrated is age-dependent. Women of repro- 2–3 years of follow-up. that a substantially lower propor- ductive age have a low incidence in ● Qifang et al. (1994) [532] re- tion of users of drospirenone con- comparison to the overall incidence in viewed data on blood pressure taining OCs started antihyperten- the population (< 20 years < 1%; age changes and hormonal contracep- sive treatment compared to users 20–39 4,6%; age 40–49 15,6% of tives. The authors found that many of other OCs [152]. cases per 100,000 women years) cross–sectional and longitudinal (EpiDatabase® http://pidb.khapps.com studies demonstrated that the use – Current healthy users: According to accessed August 2, 2011). of combined OCs containing 50 µg a review of the IHS [311], increases – Within several countries regional dif- or more estrogen could induce in blood pressure are known to occur ferences in the prevalence of arterial a rise in blood pressure averaging in women taking OCs. A 1989 World hypertension were seen, especially 6 and 2 mmHg for systolic and dia- Health Organization (WHO) study due to environmental and socioeco- stolic pressure, respectively. Simi- [654] comparing 704 women younger nomic factors [367, 368, 509]. lar results were observed in a than 35 using a combined OC (EE WHO multicenter trial [638]. 50 µg/levonorgestrel 250 µg) to 703 Important risk factors for the devel- – Progestins and their dose in rela- women using a non-hormonal intra– opment of arterial hypertension are tion to hypertension uterine device (IUD) reported higher [582]: ● Initial data on the relationship be- systolic and diastolic blood pressures – Age tween progestin dose and arterial among those receiving OC. Data from – Ethnicity hypertension have been provided the Nurses’ Health Study [91] have – Overweight or obesity, especially in by the Royal College of General shown a relative risk of approxi- children and teenagers Practitioners Oral Contracep- mately 1.8 for the development of – Gender tive Study (1977) [567]. Three hypertension in women receiving low – Unhealthy lifestyle (high-calory in- COC brands containing the same dose combined OCs. Increasing pro- take, high-sodium intake, low physical dose of the same estrogen (50 µg gestin doses were associated with a activity, smoking habits, alcohol con- EE) and different doses of the higher risk of hypertension; the low- sumption, long-lasting stressors), and same progestin (1 mg, 3 mg and est risk occurred in women receiving – Positive family history of essential 4 mg norethisterone acetate) were triphasic OCs, which have the lowest hypertension. analyzed. Based on about 27,000 total progestin dose. The superimposed risk for arterial hy- woman years (WY) of exposure – In a systematic review, Curtis et al. pertension in combination with oral and 294 cases of hypertension the (2006) [317] addressed the use of contraceptive uses can be attributed to: authors were able to show a dose– combined OC among women with ● Combined oral contraceptives: dependent increase in the inci- hypertension. Based on 25 trials, the Most OCs appear to raise the blood dence of hypertension: 1 mg authors concluded that hypertensive pressure in nearly all women [255]. NETA, 8.2 cases/1000 WY; 3 mg users of combined OCs were at higher

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 89 Oral Contraceptive Pills

risk for stroke and acute myocardial these findings cannot be extrapolated underlying risk factors for coronary infarction (AMI) than hypertensive to all progestins. For some progestins artery disease, such as hypertension, non-users, but that they were not at a dose-dependent effect of increasing as has been shown by numerous stud- higher risk for venous thromboembo- arterial blood pressure has been ies [128, 210, 513, 555, 591, 626, lism (VTE). Data from two studies shown. 743]. suggested that women with hyperten- Combined oral contraceptives: Most of the excess risk of MI related sion on combined OCs may have fur- In some women, the use of COC leads to COCs is attributed to their use by ther increases in blood pressure, but to a reversible increase in blood pres- smokers older than 35 years; the risk reviewers found these studies to be of sure. The risk of hypertension is of MI is not increased with COC use low quality. Women who did not have higher for older high dose estrogen in nonsmoking women without car- their blood pressure measured before and progestin formulations. The ini- diovascular risk factors such as hy- starting combined OCs were at higher tial assessment of arterial blood pres- pertension. risk for ischemic stroke and AMI than sure (BP) before starting COC use is – Past users: Former users do not have those who had a blood pressure meas- essential; women whose BP had not an increased risk of myocardial in- urement, although the same was not been taken were at a higher risk for farction. true for hemorrhagic stroke or VTE. ischemic stroke and myocardial in- – Regimen: Evidence for important farction than those who had a BP differences in the risk of myocardial – Past users: The risk of elevated measurement [137]. infarction between different formula- blood pressure and the increased risk A regular assessment of the blood pres- tions of OC is weak and contradic- of arterial hypertension quickly de- sure is recommended throughout the pe- tory. creases with cessation of the oral con- riod of OC use. Women with medically – EE-dose: There is little evidence that traceptive use [91]. A large prospec- treated hypertension may use low dose lowering the estrogen dose leads to a tive study of the same working group oral contraceptives under regular blood lower risk of arterial on the relationship between past, pre- pressure control – special recommenda- [637]. gravid OC use and the risk of preg- tions and restrictions must be consid- nancy-induced or -related hyperten- ered. – Progestins: sive disorders did not show conclu- The progestin type in COCs as well as sive results. The RR for gestational 2.4.2.2.2.2. Myocardial Infarction (MI) the estrogen dose has an impact on the hypertension was lower than in the Prevalence: According to the data of the risk of MI 70]. control group of never-users (0.7) but Framingham Heart Study, the inci- In a community-based, case-control for recent use of COC and pre- dence of a MI over a 10 year follow- study, Dunn et al. 1999 [162] found eclampsia, a RR of 1.3 was shown up was 5.2/1000 in women between that MI risk was similar in women [644]. the age of 35 to 44. The incidence of who received COCs containing deso- MI was eight to nine times higher in gestrel or gestodene and in women Summary: men and women aged 55 to 64 years. who received COCs containing nor- Incidence: The incidence of arterial The prevalence and detection rate of ethisterone or levonorgestrel. hypertension in young women is low MI in women has increased in the last In contrast, in another case-control and increases with age up to the high- 30 years [363]. study, Tanis et al. (2001) [637] ob- est risk for women between 40–49 Risk factors: Studies of myocardial inf- served an increased risk of MI with years. arction have found inconsistent re- levonorgestrel-containing COCs but Risk factors: Several well known risk sults due to confounding risk factors no significant increased risk with factors for high blood pressure have (particularly smoking and raised desogestrel- or gestodene-containing been described and are the focus of blood pressure) in the populations COCs in comparison to non-users. preventive measures. As a result of in- studied. Age is an important factor, An aggregated analysis of 22 studies creasing risk factors especially in de- especially for women who have a [624] including 4 metaanalyses indi- veloped countries, prehypertension considerable increase of MI risk after cated that so-called third generation and hypertension are on the rise in menopause. OCs might have a lower risk com- women of reproductive age. pared to so-called second generation Estrogens: Estrogens seem to aggravate Combined oral contraceptive users: OCs (OC with second generation pro- the effect of progestins in COC in a – Current healthy OC users: Findings gestins). Given the methodological dose-dependent manner. COC with from several early case–control stud- limitations of the individual studies, higher EE (50 µg and higher) lead to a ies suggested that the risk of MI was however, it is very difficult to differ- significant and clinically relevant in- two to four times greater in women entiate between causation, bias and crease in arterial blood pressure who currently used COCs than in residual confounding. This overview (about 5% of women with arterial hy- non–users [443, 444, 445, 446, 447, of seven controlled observational pertension). Modern OC have a less 606, 626]. studies confirms that OC containing pronounced effect [91]. Women with additional CVD risk fac- third generation progestins do not Progestins: Progestin-only OCs do not tors [70]: COC use is associated with show disadvantages with regard to MI appear to increase blood pressure sig- an increased risk of MI, particularly compared with non-users of OC. The nificantly. Individual progestins have in women who smoke and are older odds ratio (OR) for MI with older specific pharmacological profiles and than 35 years and in those who have COCs was 2.18 (95% confidence in-

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terval [CI] 1.62"2.94) and 1.13 for for MI significantly favored formula- – Past users: Former users of COCs do newer COCs (95% CI 0.66- 1.92) tions containing desogestrel or gesto- not have an increased risk of ischemic comparing COC users with non-us- dene vs. those containing norgestrel stroke. ers. The estimated OR for MI signifi- or levonorgestrel (0.62; 95% CI 0.38– – Regimen: There is insufficient infor- cantly favored formulations contain- 0.99). mation to determine major differ- ing desogestrel or gestodene vs. those ences in the risk of ischemic stroke containing norgestrel or levonor- 2.4.2.2.2.3. Ischemic Stroke (Cerebro- between products. gestrel (0.62; 95% CI 0.38"0.99). The vascular accident, CVA) – EE-dose: aggregate data and the continuing Prevalence and Definition: Past studies suggest that the use of replication of findings allow the con- – The symptoms of a cerebrovascular COCs with > 50 µg EE increases the clusion that there is a benefit of newer accident (CVA) are caused by cell and risk of ischemic stroke more than compared with older combined OC. tissue damage in the brain due to im- low-dose preparations. Data from recent studies of the car- paired blood supply. The causes of the A critical evaluation of 36 studies de- diovascular risks associated with impaired blood supply can be the for- scribing 20 distinct populations [86] COCs overall and specific COC for- mation of a blood clot (thromboem- found a modest association between mulations are summarized by Shufelt bolic, ischemic) or the rupture of the ischemic stroke and COCs containing and Bairey Merz (2009) [595]. arteries (hemorrhagic). less than 50 µg EE. However the au- – A low risk for a CVA in young healthy thors pointed out that the association Summary: women has been reported. According is tenuous given the low magnitude of Incidence: There is a low incidence of to figures from the CDC in the US in the odds ratios, severe methodologi- myocardial infarction in young healthy 2005, the prevalence of stroke in cal limitations, and – in contrast to the women. It rises with age to up to 40 women and men under 45 years was case-control studies – odd ratios of cases per 100.000 woman years for 0.8% whereas in the age-group of 45– less than 1.0 in cohort studies. women between 40–49 years of age. 65 years, the prevalence increased to – Progestins: No consistent differences 2.7%. The overall prevalence for between second and third generation Risk factors: The following important males and females was reported to be progestins were found. primary risk factors for the MI have been comparable (2.7 vs 2.5%), the inci- identified: age, hyperlipidemia, diabetes dence in whites was lower compared Summary: mellitus, hypertension, and a family his- to multiracial and black persons Prevalence: Healthy women of repro- tory of arterial atherosclerosis. Espe- [296]. ductive age have a low prevalence of cially several life-style habits such as – Increasing age, genetic thromboem- CVA. smoking, high-calory diet, chronic stress bolic predisposition and life-style are Risk factors for CVA are, in particular, also contribute to an increased risk for the predominant risk factors for athe- age, familial risk for thromboembolic MI. rosclerosis and CVA. Concurrent me- incidents and life-style factors like dical risk factors for ischemic stroke cigarette smoking, hypertension as well Combined oral contraceptives: are diabetes and atrial fibrillation. as special diseases like migraine with – Current users: Findings from sev- Special risk factors for CVA in combi- aura. eral early case-control studies sug- nation with OC: Current users of low Combined oral contraceptives: gested that the risk of MI was two to estrogen dose COCs appear to have an – Overall, no convincing evidence has four times higher in women who cur- increased risk of ischemic stroke com- been found that the use of low–dose rently used COCs than in non-users. pared to non-users if they are 1) 35 years COCs increases the risk of ischemic – COC use is associated with an in- of age or older, 2) cigarette smokers, 3) stroke in women younger than 35 creased risk of MI, particularly in hypertensive, and 4) have a history of years of age who do not smoke or suf- women who smoke and are older than migraine with aura. fer from hypertension. 35 years and in those who have under- Migraine itself is an outstanding risk – Current users of low estrogen dose lying risk factors for coronary artery factor for CVA. Evidence from case– COCs appear to have an increased disease, such as hypertension. control-studies and later a meta–analysis risk of ischemic stroke compared to – The risk of MI is not increased by show that COC users with a history of non-users if they are 35 years of age COC use in nonsmoking women migraine have a clearly elevated risk or older, smoke, are hypertensive, without cardiovascular risk factors. compared to users without migraine and have a history of migraine with – Past users have no increased risk for (Curtis) and an up to 14-fold increased aura. MI. risk of ischemic stroke compared to OC – Dosage: The aggregate data and the non–users without migraine [87]. In 2.4.2.2.2.4. Hemorrhagic Stroke continuing replication of findings combination with oral contraceptives, Prevalence: suggest a benefit of newer compared especially migraine with aura has an in- – Hemorrhagic stroke is a subcategory with older combined OC [624]. creased risk of CVA and should clearly of CVA with intracranial bleeding af- – Progestins: No conclusive relevant be considered as a contraindication for ter primary rupture of a vessel or sec- differences between various proges- COC [87, 138, 232, 387]. ondary to an ischemic stroke. Similar tins, dosages, combinations and regi- Combined oral contraceptive users to ischemic stroke, a low risk for mens have been shown. The only (Collaborative Group for the Study of hemorrhagic stroke has been reported clear finding is that the estimated OR Stroke in Young Women, 1973) [108]: for young healthy women.

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 91 Oral Contraceptive Pills

Risk factors: Incidence: Dosage of ethinyl estradiol in relation – In theory, similar risk factors to – The overall incidence of DVT in the to the risk of VTE ischemic stroke, such as hypertension United States is estimated to be 1.2 Estrogen dose: The causal association and age, apply. Additionally genetic cases per 1000, with the risk continu- between very high doses of estrogen and factors determining vessel wall ab- ously increasing with age. cardiovascular side effects – and in par- normalities in the brain and hemo- – Differences in incidence of VTE have ticular thromboembolism – is well estab- static parameters play a role in the been shown for gender, ethnicity and lished [648]. Furthermore, it has been pathogenesis of hemorrhagic stroke. race [706]. demonstrated that the VTE risk is influ- – In a prospective study, smoking and enced by the EE dosages typically used the risk of hemorrhagic stroke in Data on VTE risk in combination with for COCs [423, 562]. women was evaluated and tobacco OC: Various studies have consistently – Dose reduction from 50 to 30–40 μg users had a RR of 2–3 in comparison found an increased risk of venous throm- EE: A risk reduction by reducing EE to women who had never smoked boembolism among current users of low from 50 to 30–40 μg has been shown [401]. estrogen dose COCs with a relative risk even if the study results have some- within the range of 3–6 [228]. times been contradictory [423, 724]. OC and hemorrhagic stroke: The first report suggesting a link be- Epidemiological studies have shown – However, no evidence exists that OC tween use of combined oral contracep- that the incidence of venous throm- users with these risk factors have a tives (COCs) and pulmonary embolism boembolism (VTE) in women without higher risk of hemorrhagic stroke was published in 1961 [357]. Since then, other risk factors for VTE using com- than non-OC users with the same risk there have been more than 70 epidemio- bined oral contraceptives with low factors. logical studies investigating the relation- estrogen content (< 50 µg EE), is 20 to – EE: No evidence of a dose-dependent ship between COC use and myocardial 40 cases per 100,000 woman-years. risk. infarction, stroke or venous thromboem- However, in the typical population of – Progestins: No evidence of a differ- bolism [230]. OC users, the incidence is about 90 ential risk for second and third gen- Risk factors: The VTE Risk is substan- cases per 100,000 woman-years [149]. eration progestins. tially elevated among women with vari- Combined oral contraceptives: ous inherited clotting factor defects and Dose reduction of 30–40 to 20 μg EE: – Current users: The critical evaluation women with a family history of VTE. In The further reduction of EE to 20 µg of 30 studies mentioned above [86] did clinical practice, investigating the family EE can lead to a further, but only not find any association between history may be clinically more useful slight reduction in the risk of VTE hemorrhagic stroke and use of COC. and cost-effective for risk assessment [149, 422]. – Past users: Former users of COCs do than thrombophilia testing. The risk of – Dose reduction of 30–40 μg of EE not have an increased risk of VTE in women with a factor V Leiden COC vs EE free OCs: The data of hemorrhagic stroke. mutation increases 15-times (hetero- Lidegaard et al. (2009) [422] suggest Summary: zygous) or even more than 100 times in that progestin-only pills taken by Prevalence: Data suggest a low overall the high risk case of a homozygous mu- women of fertile age are not associ- risk for hemorrhagic stroke in young tation. ated with an increased risk of venous healthy women. Considering the prevalence of throm- thromboembolism: POP containing Risk factors: There is no evidence that bophilia and the low prevalence of VTE levonorgestrel or norethisterone: RR OC users with risk factors like hyperten- in non-users of combined oral contra- for VTE: 0.59 (0.33–1.03) (data base: sion, diabetes mellitus or a family history ceptives, the absolute risk remains low. 65.820 woman-years) or 75 µg deso- have a higher risk of hemorrhagic stroke The findings from the TREATS study gestrel RR 1.12 (0.36–3.49) (Source: than non-users with the same risk factors, show that selective screening based on 9.044 woman-years). However, we but these risk factors must be evaluated prior VTE history is more cost-effective must point out that although these re- carefully before prescribing an oral con- than universal screening [727]. Further- sults reflect typical use there is no traceptive. more, the presence of several cardiovas- hard evidence that these results can be Combined oral contraceptives: cular risk factors (such as age and obes- extrapolated to women with signifi- – No association between hemorrhagic ity) leads to an over-additive increase in cant risk factors. stroke and use of COC. COC users. – Risk assessment for COC with – No data on a dose-dependent risk as- Combined oral contraceptives: estradiol or estradiol valerate: sociated with EE – Current users: Current users have a Compared with EE-containing prod- – No studies showing a differential risk 3-6-fold increased risk of DVT com- ucts estradiol and estradiol valerate for second and third generation pared to non-users. Especially in the lead to lower liver enzyme induction progestins. first year of use the risk is elevated, and reduced influence on hemostasis. but continues to be increased until the At present it is unclear whether this 2.4.2.2.3. Venous Disease OC use is stopped [228]. theoretical advantage will actually 2.4.2.2.3.1. Venous Thromboembolism – Past users: The increased risk of lead to a lower incidence of VTE. (VTE) VTE normalizes within 3 months af- – Progestins and their dose in rela- Venous thromboembolism is a collective ter cessation of OC use. Former users tion to the risk of VTE: term for deep (DVT) of COCs do not have an ongoing in- – The influence of different progestins and pulmonary embolism. creased risk of ischemic stroke. on the risk of VTE is controversial.

92 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

Levonorgestrel is mostly used as the – Chlormadinone acetate: Regarding able data, including some further re reference for comparison between chlormadinone acetate (CMA), there analyses and information on additional different progestins relative to CVD. is no evidence of an increased risk of analyses regarding the risk of venous According to the best currently avail- VTE compared to COC with levonor- thromboembolism (VTE) associated with able studies [149] the VTE incidence gestrel [697]. Conard et al. (2004) drospirenone containing combined oral of levonorgestrel-containing COCs evaluated the impact of antigon- contraceptives (COC), such as Yasmin with less than 50 µg EE is approxi- adotropic doses of CMA (10 mg/day) and Yasminelle. Altogether seven epide- mately 8 cases per 100,000 woman- on the recurrence of DVT in women miological studies [422, 674, 353, 504, years. This number represents the risk with a previous history of DVT and/or 586, 150, 153] analysed/evaluated the for the typical OC user population; hereditary thrombophilia [116]. The association between drospirenone-con- however the risk in each individual incidence of DVT was similar in taining COC and VTE. case may be different due to the women using contraception with and strong age-dependent risk. without CMA. This retrospective The assessment has not changed the con- – The incidence rates for norethiste- study still needs to be confirmed by clusion that the risk of VTE associated rone, norethisterone acetate and nor- further prospective studies. with any COC (including those contain- gestimate are similar to that for levo- – Dienogest: This also applies to EE- ing drospirenone) is very small. The norgestrel [422]. containing COC with dienogest [153]. PhVWP concluded that the data showed The studies published in the mid- – Drospirenone: For drospirenone the that drospirenone-containing COC are 1990s showed a higher risk for the so- results are also contradictory. Two associated with a higher VTE risk than called third-generation progestins, large prospective cohort studies 149, levonorgestrel containing COC and that gestodene and desogestrel compared 586], and a German case-control the risk may be similar to that for COC to levonorgestrel (see meta-analysis study [153] showed no increased risk, containing desogestrel or gestodene. The of Kemmeren et al. 2001) [370]. whereas a retrospective cohort study PhVWP recommended that the product Studies that adjusted for the time de- in Denmark [154] and a Dutch case– information for all drospirenone contain- pendence of risk (higher risk in the control study found a modestly in- ing COC should be updated to reflect first months after initially starting OC creased risk compared with levo- these conclusions. There is no reason for use or restarting after a break) and ad- norgestrel-containing preparations women to stop taking drospirenone con- justed quantitatively correctly for dif- [673]. The latter two studies have sig- taining COC such as Yasmin and ferences in age showed no significant nificant methodological bias [154, Yasminelle or any other COC. In Ger- differences between the progestins of 590]. The Dutch study was not statis- many the BfArM (Federal Institute for different generations. However, due tically significant and neither the Pharmaceuticals and Medical Prod- to the methodological shortcomings cases nor the controls were repre- ucts) (2011) [288] published a similar of all the available studies, no defini- sentative. In the Danish study, short– statement on their homepage. tive conclusions can be drawn about a term use and long–term use had been causal relationship. For the time be- misclassified to a significant degree Summary: ing, the discussion is ongoing [243, and no data have been published on – The incidence of VTE in the general 422, 590, 674]. important risk factors. In addition, an population is about 1 /1000 (US data). – Cyproterone acetate: The results for independent validation study demon- Oral contraception is associated with cyproterone acetate (CPA) are contra- strated that about 30% of the diag- a 3–6 fold increase of VTE risk. dictory. This applies even to the re- noses that were adopted by the au- – Additional risk factors for deep ve- sults from the one and the same work- thors from the Danish patient registry nous thrombosis should be taken into ing group, which have been evaluated were probably incorrect [589]. Prob- account when counseling on contra- at different times and with different ably drospirenone when compared ceptive methods. General screening methodologies but using the same with levonorgestrel poses no in- of genetic thromboembolic risk fac- data source. Analysing the Danish pa- creased risk, although a small in- tors is not recommended. A notable tient registry in 2003, Lidegaard re- crease (or theoretically, a slightly lo- high-risk situation is the familial pre- ported an incidence of 31 VTE per wer risk) cannot be ruled out. disposition for VTE events. 100,000 woman-years with a confi- In summary, the VTE risk of drospi- – On the whole, it should be noted that dence interval of 13–49 [422]. Six renone- versus levonorgestrel-contain- the use of any combined oral hormo- years later the point estimates of the ing COCs cannot be conclusively ascer- nal contraceptive (COC) is always as- incidence rate were 71 VTE cases per tained. The studies with the best method- sociated with an increased VTE risk. 100,000 woman-years – clearly out- ology do not indicate a higher risk for The risk is dependent on the estrogen side the confidence interval of the drospirenone, but these studies also have dose and might be modulated by the 2003 analysis. In the same period, the methodological limitations and cannot choice of progestin. Whether a clini- relative risk compared with levonor- exclude a slight increase in risk. cally relevant difference in the risk of gestrel increased from 0.7 to 1.9. venous thromboembolism exists for These differences are not easily ex- This is also reflected in a statement by different progestins is currently the plained by chance and show the major the PhVWP (Pharmacovigilance Work- subject of debate. methodological difficulties in imple- ing Party) of the European Medicines menting and evaluating studies on Agency (EMA) [729] (May 26th, 2011), Table 2 shows an evaluation of differ- VTE risk in OC-users. which was based on a review of all avail- ent hormonal contraceptives and ve-

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 93 Oral Contraceptive Pills Table 2. Classification of contraceptives according to the risk of VTE in healthy women of reproductive age without additional risk factors (such as obesity, immobilization, positive family history of cardiovascular disease, cigarette smoking). Rabe et al. Contraception and Thrombo- philia. See this issue, page 204. Risk Age Incidence Contraceptive method/ Published Studies Ongoing Studies (Years) (VTE/10,000 Population group women years)

Reference ≤ 19 1–2 Healthy, non-pregnant women of child- Lidegaard 2009 [422]: INAS-OC and INAS-SCORE 20–29 2–3 bearing age not using a contraceptive I = 3.0 (2.9–3.2); Ex = 4813 TWY (EURAS-type studies; end 2013 and 2014, 30–39 3–4 respectively) 40–49 5–7 Non-hormonal contraceptive methods Dinger 2007 [150]: – tubal sterilization I = 4.4 (2.4–7.3); Ex = 65 TWY – condoms, spermicides – behavioral methods Review Article: Heinemann 2007 15–49 3–4 – copper IUDs

Unchanged 15–49 3–4 Progestin-containing contraceptives Lidegaard 2009 [422]: or (slight increased risk cannot completely Levonorgestrel-IUS EURAS-IUD Slightly be excluded in comparison to non-hormo- I = 3.4 (2.3–4.7); Ex = 101 TWY (EURAS-type study; ends 2012) increased nal contraceptive methods; therefore non- Progestin-only pill LASS hormonal methods should be preferred for I = 2.0 (1.1–3.3); Ex = 75 TWY (EURAS-type study; ends 2011) women with a history of thrombophilia) – Levonorgestrel-IUS – Progestin-only pill – Progestin-only ovulation inhibitor – Progestin depot injections

Moderately ≤ 19 3–4 Combined oral contraceptives with < 50 µg increased 20–29 5–8 Ethinyl estradiol and – Level 1 30–39 8–10 – Levonorgestrel (LNG), Norethisteron, Lidegaard 2009 [422]: LASS 40–49 15–22 – Norethisteron acetat or Norgestimate I = 5.5 (4.7–6.3); Ex = 367 TWY (EURAS-type study; ends 2011) – (NGM) (underestimation due to misclassifi- 15–49 6–10 cation of current duration of use and other reasons) Dinger 2007 [150]: I = 8.0 (5.2–11.7); Ex = 31 TWY

– Chlormadinone acetate (probably no Waldmann-Rex 2009: No EURAS-type study – higher risk than with LNG-containing I = 2.4 (0.9–5.2); Ex = 25 TWY – COCs; however, a slightly higher risk (underestimation due to – cannot be excluded) methodological short-comings)

– Dienogest (probably no higher risk than Dinger 2010 [153]: INAS-SCORE – with LNG-containing COCs; however a OR vs LNG: 1.0 (0.6–1.8); 95 Ca/303 Cn (EURAS-type study; ends 2014) – slightly higher risk cannot be excluded)

– MPA depot injection (classification is van Hylckama, Vlieg et al. 2010: No EURAS-type study – based on a methodologically limited OR* 3.6 (1.8–7.1); 20 Ca/15 Cn – study with a limited number of cases (*vs. non-use of hormonal contra- – and controls; overestimation of risk ceptives; OR vs. LNG: ~1) – compared to other hormonal – contraceptives possible)

Combined oral contraceptive pills with INAS-SCORE Estradiol valerate and Dienogest (less (EURAS-type study; ends 2014) influence on hemostasis compared with Ethinyl estradiol/Dienogest; however, risk assessment should be based on the VTE- incidence of Ethinyl estradiol/Dienogest as long as robust data are not available)

NuvaRing® (provisional classification based TASC on interim results from the TASC study) (EURAS-type study; ends 2012)

– Level 2 15–49 6–14 Combined oral contraceptives with < 50 µg Ethinyl estradiol and – Drospirenone (DRSP) (inconsistent study Lidegaard 2009 [422]: LASS – results; in contrast to retrospective I = 7.8 (6.4–9.5); Ex = 131 TWY (EURAS-type study; ends 2011) – database studies 2 prospective cohort (no substantial missclassification of INAS OC – studies and 1 retrospective field study duration of use; potential overestimation (EURAS-type study; ends 2011) – did not show an increased risk compared of risk compared to LNG [see above]) – to LNG-containing COCs; based on – currently available data a slightly Dinger 2007 [150]: – increased risk is possible) I = 9.1 (5.9–13.3); Ex = 29 TWY

Dinger 2010 [153]: OR vs LNG: 1.0 (0.5–1.8); 85 Ca/281 Cn

Jick et al. 2011 [353]: OR 2.2 (1.5–3.4); 166 Ca/550 Cn

Parkin et al. 2011 [128]: OR 2.9 (1.1–7.4); 57 Ca/176 Cn

– Desogestrel (DSG), Gestoden (GSD) or Lidegaard 2009 [422]: LASS – Cyproterone-acetate (CPA) (risk of VTE in DSG/GSD (EURAS-type study; ends 2011) – comparison with LNG-containing prepara- I = 6.8 (6.5–7.2); Ex = 2008 TWY – tions scientifically controversial, however CPA – a slightly to moderately higher risk is I = 7.1 (5.7–8.7); Ex = 127 TWY – possible) (less substantial underestimate of the risk compared to LNG [see above]) Case-control studies with and without adjustment for duration of use showed ORs of ~ 2 and ~ 1. Numerous review articles available; the most balanced representation being the decision of the High Court of Justice in 2002 [132]

Evra contraceptive patch (VTE risk Dore 2010: No EURAS-type study compared to COCs with LNG or NGM OR vs NGM: 2.0 (1.2–3.3); 102 Ca/353 Cn controversial; a slightly to moderately increased risk is possible) Jick 2010: ORs vs LNG from 2 sources 46 Ca/207 Cn & 97 Ca/382 Cn: 2.0 (0.9–4.1) & 1.3 (0.8–2.1)

Substantially 15–49 20–30 Pregnancy and the first three months Heit 2005: No EURAS-type study increased after childbirth; risk after cesarean section I = 29.3 (23.8–35.6); Ex = 50 TWY significantly higher than after spontaneous delivery Lidegaard 2011: RR vs ‘non-pregnant non-users’ 10.6 (9.4–12.0); 265 Cases

Ex = Exposure in 1000 woman-years; Ca = Number of relevant cases in a case control study; I = Incidence of VTE/10,000 WY with 95% CI; Cn = Number of relevant controls in a case control study; OR = odds ratio; RR = relative risk; TWY = 1,000 woman-years; * cases/controls

94 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

nous thromboembolism risk in the breast was 61 years. No breast induced abortion, breast implants, healthy women of reproductive age cancer was diagnosed under the age chemicals in the environment, to- without additional risk factors com- of 20; 1.9% between 20 and 34; bacco smoke, night work. pared to pregnancy and childbirth 10.5% between 35 and 44; 22.6% be- (see also the review by Rabe et al. tween 45 and 54; 24.1% between 55 – Epidemiological data [96] “Contraception and Thrombophilia” and 64; 19.5% between 65 and 74; ● The first report about the associa- in this supplement). 15.8% between 75 and 84; and 5.6% tion between breast cancer and oral at 85 and older. contraceptives was published by The evaluation of different hormonal The age-adjusted incidence was Pike et al. (1981) [517]. contraceptives and venous throm- 122.9 per 100,000 women per year. ● Meta-analysis and re-analysis: boembolism risk in healthy women of These rates are based on cases diag- In 1996, the Collaborative Group reproductive age without additional nosed in 2003–2007 from 17 SEER on Hormonal Factors in Breast risk factors compared to pregnancy geographic areas. Cancer published a re-analysis of and childbirth is published in a review – Multiple risk factors have been worldwide epidemiologic data on by Rabe et al. on “Contraception and analyzed in various reviews [i.e. a possible relationship between Thrombophilia” in this supplement. 598] and can be classified according OCs and the diagnosis of breast to their importance and the preventive cancer. The re-analysis involved 2.4.3. Oral Contraceptives and Cancer profile. 54 studies (90% of all epidemio- Cancers of the breast, lung and colon are logical studies), a total of 53,297 among the top ten causes of death of Risk factor classification according women with breast cancer and older women globally. The incidence to their importance [184]: 100,239 women without breast (new cases) of breast cancer is much ● Strong risk factors are older age, cancer [110], Oxford meta-analy- higher in high-income countries com- family history, and previous breast sis [83], Mayo Clinic (meta-analy- pared to low- and middle-income coun- cancer. sis) [359]. tries, but mortality is similar. This is due ● Moderate risk factors are density Large cohort-studies: Nurses’ (co- to the availability of better treatment in of the breasts on mammogram, bi- hort) [226], RCGP (cohort) [231], the high-income countries. For lung and opsy abnormalities, and exposure Oxford Family Planning (cohort) colon cancer, both incidence and mortal- to radiation. [690], Women’s CARE [448], ity are currently higher in high-income ● Other risk factors are age at time Women’s Lifestyle and Health countries. Globally, 71% of lung cancer of reproductive events, pregnancy study (cohort) [398]. deaths are caused by tobacco use. and , hormone re- ● Definition of risk: “Risk of having placement therapy (HRT), height breast cancer diagnosed” is differ- According to the WHO [330], cervical and weight, alcohol consumption, ent from “life–time risk” for breast cancer is the second most common type presence of other cancers, miscel- cancer. The question why OC-us- of cancer among women worldwide, laneous factors. ers have a higher detection rate of with virtually all cases linked to genital ● The risk is decreased by removal breast cancer (earlier detection of infection with the human papillomavirus of the ovaries, lifestyle changes, preexisting tumors) or a higher (HPV). Almost 80% of cases today and medication, and early detection. lifetime risk (additional new tu- an even higher proportion of deaths from Risk factors (American Cancer So- mors in OC users) has not been an- cervical cancer occur in low-income ciety) [9]: swered until now. A stimulation of countries, where access to cervical can- ● Unchangeable risk factors: gen- preexisting breast cancer is as- cer screening and treatment virtually der, aging, genetic risk factors, sumed, rather than the induction of does not exist. family history of breast cancer, mutagenesis and new tumors (la- personal history of breast cancer, tency between toxic exposure and Some recent reviews deal with hormonal race and ethnicity, dense breast tis- clinically detectable carcinoma: contraception and cancer in women [96, sue, certain benign breast condi- 10–15 years). 231], as well as previous reports of the tions, lobular carcinoma in situ, IARC monograph (1999) [278] , the menstrual periods, previous chest – Current users [96]: IARC monograph (2007) [336], the radiation, expo- ● In the majority of studies there has ESHRE Capri Workshop Group sure been no increase in the risk of (2005) [359, 608, 649, 690]. ● Lifestyle-related factors and breast cancer reported in current breast cancer risk: having chil- OC users. 2.4.3.1. Breast Cancer dren, recent oral contraceptive use, ● Long duration of OC use at a The worldwide incidence of breast can- after menopause, young age before the first full- cer is increasing; it is estimated that one breast-feeding, alcohol, being term pregnancy seems to be the out of ten women will suffer from breast overweight or obese, physical ac- most important risk factor, as cancer during their lifetime. tivity hormones act on a less differenti- ● Factors with uncertain, contro- ated tissue. – US National Cancer Institute versial, or unproven effect on ● The number of events attributable (SEER) [280]: From 2003–2007, the breast cancer risk: diet and vita- to OC use remains below 1% of the median age at diagnosis for cancer of min intake, antiperspirants, bras, total number of breast cancers and

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7% for premenopausal breast can- human epidermal growth hormone Special screening programs for wo- cer. This risk calculation is based receptors. Tumor growth, treatment men with BRCA1/2 have been estab- on the RR of the fraction of breast options and prognosis are linked to lished. cancer attributable to OC in France the expression of these receptors. Reviews and meta-analysis: [82]. In postmenopausal women, the lower – IACR Monographs on the Evalua- – Risk in past users: The risk de- incidence of HRT use recently led to a tion of Carcinogenic Risks to Hu- creases progressively after cessation lower rate of diagnosed breast cancer mans (2009) [278] of OC use. cases. – Meta-analysis: Collaborative Group – First generation of OC formula- Oral contraceptives: on Hormonal Factors in Breast tions. The increase in the RR is low, The conclusions below are based on Cancer (1996) [110]. heterogeneous and may be linked to multiple meta–analyses (e.g. Collabo- – Large cohort-studies: Nurses’ (co- high dose first generation of OC for- rative Group on Hormonal Factors in hort) [226], RCGP (cohort) [231], mulations. Variations may be due to Breast Cancer 1996) [110], Oxford Oxford Family Planning (cohort) study design and disease heterogene- meta-analysis [83], Mayo Clinic (meta- [690], Women’s CARE [448], Wom- ity. Screening or recall bias cannot be analysis) [359]. en’s Lifestyle and Health study (co- excluded [448, 556, 592]. – Current users at a young age: Long- hort) [398]. – OC-regimen: None of these studies term OC use at a young age before the – Extended reviews: Cibula et al. provided evidence for any relevance first full-term pregnancy seems to be (2010) [96] of the OC composition on breast can- the most important risk factor. Further references: cer risk. – Risk: The risk of a contemporarily di- – The ESHRE Capri Workshop – BRCA1/2 mutations: According to a agnosed breast cancer increases, but Group (2005) [649] recent review by Iodice et al. (2010) not the lifetime-risk for breast cancer – National Cancer Institute (US) [343] oral contraceptive use has been itself. [292] associated with a moderately in- – Risk in past users: The RR for BC creased risk of breast cancer, which risk is increased; this effect disappears 2.4.3.2. Cervical Cancer tends to decline progressively after progressively after stopping OC use. Incidence: US National Cancer Insti- termination of use. In addition, a re- – First generation OC formulations. tute (SEER) [281]: From 2003– duced risk of ovarian cancer in The increase in the RR is low and het- 2007, the median age at diagnosis for women who had not been selected for erogeneous. It is likely linked to high cancer of the uteri was 48 predisposing genetic mutations was dose first generation OC formula- years. Approximately 0.2% were di- shown. The use of OCs in mutation tions. Screening or recall bias cannot agnosed under age 20; 14.5% be- carriers remains controversial be- be excluded [448, 556, 592]. tween 20 and 34; 26.1% between 35 cause of their increased risk and early – OC regimen: The large studies on and 44; 23.7% between 45 and 54; onset of breast cancer. For BRCA1/2 OC and BC risk have shown no im- 16.3% between 55 and 64; 10.4% be- carriers, the protective effect against pact of the OC composition on breast tween 65 and 74; 6.5% between 75 ovarian cancer must be taken into ac- cancer risk. and 84; and 2.4% 85+ years of age. count. COC reduce the risk of ovarian – Progestins: No specific effects of The age-adjusted incidence was 8.1 cancer without clear evidence that re- progestins currently used for oral hor- per 100,000 women per year. These cent formulations increase the risk of monal contraception on BC risk have rates are based on cases diagnosed in breast cancer in women with a germ- been found. 2003–2007 from 17 SEER geogra- line mutation in BRCA1 or BRCA2. – Studies clearly suggest that OC are phic areas. While these results are reassuring, not an initiator of breast cancer de- further prospective studies in carriers velopment and do not induce car- Etiology: are indicated. The open questions are cinogenicity, but might act as a pro- ● HPV-infection: The vast majority possible additive effects of the usage motor. Steroid hormones might of cervical cancers are caused by of other hormones and specific effects stimulate preexisting malignant cells. HPV infection. HPV is considered of different types of OCs. BRCA1/2 mutations: According to a as the main and preventable risk recent meta-analysis of Iodice et al. factor. Approximately 14 types of Summary: (2010) 343], the use of OCs in muta- HPV have been identified as a po- Incidence: The incidence of breast can- tion carriers remains controversial. tential cause of this cancer. HPVs cer is increasing globally; one of ten The meta-analysis provides evidence were found in 99% of cervical can- women will suffer from breast cancer that OCs reduce the risk of ovarian cer biopsy specimens worldwide during their lifetime. cancer without any evidence that re- [187]. Certain strains of HPV, most Hormone dependency of breast can- cent formulations increase the risk of notably HPV-16 and HPV-18, are cer: The growth of existing estrogen- breast cancer in women with a germ– especially associated with cancer sensitive breast carcinoma cells is line mutation in BRCA1 or BRCA2. of the uterine cervix and consid- stimulated by estrogens and inhibited For more information see National ered as high risk (HR) strains [57]. by , withdrawal of estro- Cancer Institute (US) [290, 291]. Long-term COC use has been gens by aromatase inhibitors and ova- Prevention: Regular cancer screening identified as a possible co-factor riectomy. Breast carcinoma cells ex- including self-examination of the that significantly increases the risk press steroid hormone receptors and breasts is strongly recommended. of cervical cancer in women who

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are positive for HPV-DNA [471]. 5–9 years 1.3 (1.0–1.9) the relative risks of cervical cancer in- More information about HPV and ≥ 10 years 2.5 (1.6–3.9) creased with increasing duration of cancer is available at the US Na- In 2007, findings from another use [23]. tional Cancer Institute [742]. pooled analysis of data from 24 stud- – Past users: The risk decreased in the ● Prevention of infection: The use ies worldwide including 16,573 meta–analysis of Appleby et al. of condoms prevents cervical HPV women with cervical cancer and (2007) [23] after discontinuation of infection – but not vaginal and 35,509 without cervical cancer sug- COC use, returning to that of never- vulvar infections. gested that the risk of invasive cervi- users 10 or more years after discon- ● Different contraceptive methods: cal cancer increased with prolonged tinuation. An association between HPV-in- duration of COC use (RR for use 5 – Bias: Study designs varied and the re- fection, cervical cancer and oral years vs never-use, 1.90; 95% CI sults showed big heterogeneity. contraception is assumed, espe- 1.69–2.13) [23]. Reviews and meta-analysis: cially as the use of other contracep- – Histology: Histological results were – IACR Monographs on the Evalua- tives like IUD/IUS does not seem broadly similar for invasive and in- tion of Carcinogenic Risks to Hu- to be linked with a higher risk of situ cervical cancers, for squamous mans (2009) [278] cervical cancer: cell and adenocarcinoma. – Meta-analysis: Smith et al. (2003) ■ Copper-IUD [136]: Four case– – Confounding factors: The results [608] control studies found no asso- were comparable in studies that ad- Further references: ciation between IUD use and justed for HPV status, number of – The ESHRE Capri Workshop Group risk for cervical cancer. No sexual partners, cervical screening, (2005) [649] trend in associations was ob- smoking, or use of barrier contracep- – National Cancer Institute (US) served with characteristics of tives. [293], National Cancer Institute, IUD use, type of IUD and histo- – Past users: The risk decreased in the US [479]. logic type of cancer. meta-analysis of Appleby et al. 2007 ■ IUD/LNG-IUS – No specific [23] after discontinuation of COC 2.4.3.3. Benign Liver Tumors and data are available. use, returning to that of never-users Hepatic Cancer 10 or more years after discontinua- – Liver cancer: Current, but not past Co-risk factors for HPV-infection tion. Consequently long-term users of OC use is associated with an in- – Chlamydial infection [607] OC should be screened for cervical creased risk of benign liver tumors – Cigarette smoking [342] cancer in specific programs. and a modestly increased relative risk – Other risk factors (American Can- Bias: However, study designs showed of liver cancer. cer Society) [11]: immunosuppres- a remarkable variety and heterogene- OC use and liver diseases (benign sion, diet, oral contraceptives, multi- ity between different studies. tumor and hepatic cancer) ple full-term pregnancies, young age – Several studies have found that OCs at the first full-term pregnancy, pov- Screening programs: Improved screen- increase the risk of liver cancer in erty, diethylstilbestrol (DES), family ing programs and initiation of vaccina- populations usually considered low history of cervical cancer tion against HPV infection during ado- risk, such as white women in the Combined oral contraceptives lescence have created a new paradigm in United States and Europe who do not The first reports about an association be- cervical cancer control. suffer from liver disease. In these tween cervical cancer and oral contra- studies, women who had used OCs ceptives were published by Peritz et al. Summary: for longer periods of time were found (1977) [510], Vessey et al., (1983) Incidence: Estimated new cases and to be at an increased risk of liver can- [692], WHO collaborative study of deaths from cervical (uterine cervix) cer [728]. However, OCs did not in- neoplasia and steroid contraceptives cancer in the United States in 2010: crease the risk of liver cancer for (1985) [708], Brinton et al., (1986) New cases: 12,200, Deaths: 4,210 women in Asia and Africa, which are [61]. [293] high risk areas for this disease. The Meta-analysis: Smith et al. (2003) Histology: The World Health Organiza- most probable explanation for this is [608] tion (WHO) recognizes two main histo- the fact that predominant risk factors, – 28 eligible studies were identified, in- logical types of invasive cancer: Squa- such as hepatitis infection, outweigh cluding a total of 12,531 women with mous carcinoma (about 85% of all the effect of OCs [735]. cervical cancer. cases) and adenocarcinoma (about 10– – Duration of use [608]: Compared 12% of all cases) [307]. 2.4.3.4. Various benign tumors and car- with never-users, the relative risks of Etiology: Cervical cancer is almost al- cinoma [311] cervical cancer increased with in- ways caused by human papillomavirus – There was no evidence of an associa- creasing duration of OC use: (HPV) infection [293] tion between OC use and lung or di- Duration of use No HPV-infection Combined oral contraceptives: gestive tract neoplasms, cutaneous < 5 years 1.1 (1.1–1.2) – Metaanalysis: [608]: 28 eligible stud- malignant melanoma, thyroid cancer 5–9 years 1.1 (1.1–1.2) ies were identified, including a total and any other neoplasms investigated ≥ 10 years 2.2 (1.9–2.4) of 12,531 women with cervical cancer. [337] Duration of use HPV-infection – Current users [608]: Compared with – The data for colorectal cancer are < 5 years 0.9 (0.7–1.2) never–users of oral contraceptives, suggestive of a favorable, protective

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effect of OC albeit in the absence of – Poorly controlled hypertension – risk creased risk of bleeding irregularities, any consistent duration or recency of exacerbation, long term risk for including amenorrhea or infrequent risk relation. A better understanding stroke, myocardial infarction bleeding, prolonged or frequent of any potential link between OC use – Treatment with anticonvulsants – effi- bleeding and unscheduled bleeding or and colorectal cancer may therefore cacy may be reduced due to drug in- spotting, and higher rates of early help making an informed choice teractions discontinuation, both overall and due about contraception [337, 402]. – Migraine , especially with to adverse events such as irregular aura and neurological symptoms – in- bleeding compared with COCs con- 2.5. Serious Adverse Events/ creased risk of stroke taining more than 20 µg EE [199]. Contraindications [339] – Diabetes – not a contraindication if no Use of combined OCs is associated with vascular disease is present, but the in- 3.1.2. Progestins an increased risk of several serious con- sulin dose may need adjusting – Classification: Progestins are com- ditions, including e.g. myocardial inf- monly classified by “generation”. arction, thromboembolism, stroke, he-  3. Various Combinations of These categories may be misleading patic neoplasia, and gallbladder disease. Estrogens and Progestins because progestins of the same gen- The absolute risk of these events is very eration often behave differently from low in women without risk factors. The 3.0. Basics of Steroids Used each other and the same progestin epidemiological data have mainly been for Hormonal Contraception may be categorized differently in dif- obtained from studies using oral contra- 3.1. Substances ferent studies, i.e., norgestimate has ceptive formulations containing higher 3.1.1. Estrogens been classified as both a second-and estrogen and progestin doses than cur- third-generation progestin. 3.1.1.1. Estrogen Type rently used. The effect of long-term, low dose OC use has yet to be deter- Ethinyl estradiol and mestranol – Biological action: Progestins dimin- mined. Most oral contraceptives have contained ish the estrogen-related stimulating See also Sabatini et al. (2011) in the EE as the estrogen component of com- effect on the endometrium by inhibit- same supplement. bined OC for more than 50 years. Ini- ing the expression of the estrogen tially mestranol, the 3-methylether of receptor. All progestins bind to the 2.5.1. Absolute Contraindications to the EE, was also used. Mestranol is metabo- . They differ in use of Combined OCs Include lized in the liver into the active EE but their relative binding strength to this – Previous thromboembolic event or this conversion process is highly vari- steroid receptor, as well as to the an- stroke, cerebral vascular or coronary able und not clearly predictable. Today drogen, estrogen, glucocorticoid and artery disease, and valvular heart dis- mestranol is used only in a few combina- receptors and sex ease with complications tions still on the market. hormone-binding globulin [393, 580]. – Major surgery with prolonged immo- In binding to a steroid receptor, pro- bilization Estradiol and its derivatives gestins may exert antagonistic, ago- – Severe hypertension Estradiol or its derivatives are used in nistic or no clinical effects. Moreover, – Headaches with focal neurologic combination with progestins for ovula- low-or high-binding affinity does not symptoms tion inhibition, to substitute estrogen de- necessarily correlate with biologic ef- – Known or suspected estrogen-de- ficiency, and to prevent intermenstrual fectiveness (Tab. 3). pendent tumor (i.e., endometrial, bleeding, leading to regular withdrawal breast cancer) bleedings. 3.2. Target Organs – Liver disease – Hypothalamic and pituitarian ef- – Cholestatic jaundice of pregnancy or 3.1.1.2. Estrogen Dosage fects: One of the progestational ef- jaundice with prior hormonal contra- – Estrogen doses do not clearly influ- fects as a basis of oral contraception is ceptive use ence contraceptive effectiveness, but the inhibition of ovulation. The ovu- Relative contraindications: the limiting factors are dose-depend- lation inhibition dosages vary be- – Pregnancy ent differences in tolerability [70]. tween different progestins. – Undiagnosed abnormal uterine bleed- ing – In a clinical study comparing COCs – Endometrial effects: At the level of – Women over the age of 35 who smoke with 20 and 35 µg of EE, cycle control the endometrium, estrogens stimu- – Obesity – Women with a BMI > 27 are and discontinuation rates were com- late endometrial cell division, at an increased risk of pregnancy if parable between the two groups. whereas progestins block this effect. they receive low dose estrogen formu- Women receiving the higher EE dose As a result of progestin action, cell lations. However, since obesity is an reported a 50% greater incidence of proliferation ceases, despite continu- independent risk factor for thrombo- estrogenic adverse events, such as ous exposure to estrogen levels, embolism, the use of higher estrogen bloating, breast tenderness and nau- comparable to the physiological formulations (50 µg) is not advisable. sea, compared with women receiving cycle,i.e. the luteal phase. Progestins – Inherited thrombophilia – Combined the lower EE dose [554]. protect from estrogen-induced hy- hormonal contraceptives should be perplasia and changes in the prolif- avoided, although routine screening – A Cochrane Library review on COCs erative status. They induce the glan- is not recommended. containing ≤ 20 µg EE showed an in- dular epithelial secretory activity

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and decidual transformation of stro- illary patterns), glandular cellularity, – Low dose pills have the least amount mal fibroblasts; these terminally dif- cytoplasmic changes, mitotic activity, of EE (15–20 µg) ferentiated cells can no longer prolif- (tumor-) angiogenesis, and increase – Regular dose pills contain 30–35 µg erate and are shed in withdrawal or decrease in cytological atypia. EE bleeding if implantation does not oc- – High dose pills have about 50 µg of cur. These effects are dependent on 3.2.1. Reduction of the Dosage of EE. the pharmacology of the progestins Ethinylestradiol or Mestranol in used, especially their type, dosage, Monophasic OCs in a 21-day Regimen Monophasic birth control pills are as ef- [474]. Monophasic pills are oral contraceptives fective in preventing pregnancies as the However, multiple changes in histo- that have the same amount of estrogen more expensive phasic OCs, which logical features occur during hormo- and progestin in each active pill in a blis- typically cause more side-effects. Low nal contraception treatment, such as ter pack. Due to the consistently high estrogen-containing, monophasic OCs different proliferatory, secretory, and hormone level in each pill, monophasic may cause less bloating or breast ten- atrophic patterns, changes in the OCs are less likely to cause side effects derness but result in more bleeding glando-stromal ratio, stromal factors that may result from fluctuating hor- complications (especially spotting). (i.e. growth factors), architectural mones. Monophasic OCs are classified Most women prefer a monophasic OC structures (i.e. cribriform and/or pap- by their estrogen level: as a first choice.

Table 3: Contraceptive progestins: pharmacological, experimental and clinical profile. According to [394, 500, 481, 482, 599, 602, 639].

Progestogens active Oral COC Used for COC on the market (hours) Halflife Ovulation inhibition dosage per day (mg/day) Endometrium transformation per cycle dosage (mg/cycle) action Endometrial Antigonadotropic action Antiestrogenic action action Estrogenic action Androgenic Antiandrogenic action Glukocorticoid- similar action Anti-mineralo action kortikoid

Progesterone + + + several minutes [304] 300 [394] 4200 [394] + + + – – (±) – – + 19-Nortestosterone derivatives Ethinyl-substituted Norethisterone + + + 8 (6–12) [304]; 7 [299] 0,4 [394] 120 [394] + + + + + – – – Norethisterone acetate + + + 8 [304] 0,5 [394] 50 [394] + + + + + – – – Lynestrenol + + + 26 2 [394] 70 [394] + + + + + – – – Norethinodrel + + + 5–14 4 [394] 150 [394] ± + ± + + – – – Ethynodiol diacetate + + + 2 [394] 15 [394] + + + + + – – – Levonorgestrel + + + 16 (8–30) [304] 5 [394] 5 [394] + + + – + – – – Norgestimate + + + 12–30 [300] 0.2 [394] 7 [394] + + + – (+) (+) – – Desogestrel + + + 27.8 ± 7.2 [298] 0.06 [394] 2 [394] (+) – 3-Keto-Desogestrel + – – 38 ± 20 + + + – (+) – – – Gestoden + + + 16–18 [301] 0.031 3 [394] + + + – (+) – – + Methyl-substituted Dienogest + + + 8–10 [492] 1 [394] 6 [394] + + –** – – + – – 19-Norprogesterone derivatives Nestorone *) non-oral route – – – 24–72 [599, 189] 0.15 [599] 0.6 + + + – – – – – Trimegestone + + + 15 [599] 0.5 [599] 0.25 + + + – – – – – acetate + + + 28–51 [599] 1.25–2.5 [599] 100 [394] + + + – – ± – – Promegestone + – – 0.5 [394] 10 [394] + + + – – – – – Dimegestone + – – 2.5 100 [394] + ± ± – – – – – 17-Hydroxyprogesterone derivatives Chlormadinone acetate + + + 25 (sd); 36–39 (md) [643] 1,7 [394] 25 [394] + + + – – ++ + – Cyproterone acetate + + + 40 [297] 1 [394] 25 [394] + + + – – ++ + – acetate + – – 34 (13–104) [304] n. a. 50 [394] + + + – (+) – + – Medroxyprogesterone acetate + – – 12–17; 30 [304] n. a. 50 [394] + + + – (+) – + – derivatives Drospirenone + + + 30 2 50 + + + – – + – + sd = single dose; md = multiple dose; * depends on delivery system; ** according to Oettel et al. (1999) [493], and Taubert and Kuhl (1995) [639] dienogest possesses action like all progestins

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High dose estrogen (150 µg mestranol had used it [358, 450, 719]. Al- High dose COCs containing 75 or 100 µg ethinyl estradiol) and pro- though FDA-approved for contra- and 150 µg estrogen led to a 6 fold gestin (several times above ovulation ceptive use, Enovid 10 mg™ was increased risk for venous throm- inhibition dosage) pills [270]: not marketed by Searle as a contra- boembolism, and the progestin ceptive. content of the pill was linked to the 1951 The progestin derivative Norethin- 1961 On February 15, 1961, the FDA development of hypertension drone was the first orally active approved Enovid 5 mg™ by Searle [568]. These data led to the reduc- substance first synthesized by the for contraceptive use. In July 1961, tion of both components: the chemists L. Miramontes, C. Searle finally began to market estrogen (EE or mestranol) – re- Djerassi, and G. Rosenkranz at Enovid 5 mg™ (5 mg norethyno- sponsible for the increased risk of Syntex in Mexico City. Norethin- drel and 75 µg mestranol) to physi- venous thrombosis – and the pro- drone is an isomer of norethis- cians as a contraceptive [450, 699]. gestin, whose dosage of up to 6 terone. 1961 The replacement of mestranol by times the ovulation inhibition dose 1956 The Harvard group of physiolo- the active substance EE was the was unnecessarily high and essen- gists, chemists, clinicians and first step of many subsequent tially responsible for the increased physiologists G. Pincus, J. Rock, modifications of COCs. Anovlar®, risk of arterial complications (arte- M.C. Chang and C.R. Garcia ex- a drug containing 4 mg norethis- rial hypertension, myocardial inf- perimented with progestins to in- terone acetate and 50 µg EE, was arction, stroke). duce an artificial state of preg- introduced in Germany by Bayer nancy. Norethynodrel and nore- HealthCare, formerly Schering. 50 µg ethinyl estradiol containing pills thindrone, the progestins used, This first European OC (Anovlar®) 1970 Successful studies were performed were contaminated with a small was already improved in compari- with EE dosages reduced from percentage of estrogen (up to 4-7% son to the pioneer US version 150 µg mestranol per tablet to mestranol). Mestranol, a methyl- Enovid™ in that the hormone dose 80 µg mestranol and 50 µg EE re- ether and an inactive pro–drug of was reduced. The marketing of spectively. EE, undergoes its first metaboli- Anovlar® was the start of a con- zation in the liver. The potency of tinuously successful track record 30 µg ethinyl estradiol containing pills 150 µg mestranol equals 100 µg of innovation in contraception. 1972 Development of low dose mono- EE [730, 308]. The suitable addi- The steroid dosages in Anovlar® phasic preparations called micro- tional dose of Mestranol to supple- were lower than in the original pills containing less than 50 µg EE ment Norethynodrel in order to Enovid™, which contained 10 mg per pill in the United States and suppress breakthrough bleeding - the first step in minimizing the Germany. The first micropill was was found, and the first oral con- hormone dose. introduced in Germany by Sche- traceptive as a combination of 1961 In the UK the first case of thrombo- ring Pharmaceuticals, Berlin (now progestins and mestranol was in- sis and pulmonary embolism in a Bayer HealthCare). troduced under the proprietary woman using Envid 10mg™ (for- 1973 The micropill Microgynon 21® name Enovid™ [518, 549]. mulation of Enovid™ in the UK) and 28® was introduced by 1957 The Food and Drug Administration was published by Jordan and Schering (now Bayer HealthCare) (FDA) approved the first hormonal Anand in 1961 [356], four years containing 0.15 mg levonorgestrel combination Enovid 10 mg™ after its approval. It took almost a and 30 µg EE. For the first time, (9.85 mg norethynodrel plus 150 decade of epidemiological studies an OC containing less than 50 µg µg mestranol) for menstrual disor- to conclusively establish an in- EE was available, establishing a ders based on data from its use by creased risk of venous thrombosis whole new class of pills called more than 600 women. Numerous in oral contraceptive users as well “micropills”. Since then, the additional contraceptive trials as an increased risk of stroke and micropill has become the standard showed Enovid to be highly effec- myocardial infarction in risk OC. Pills with higher estrogen tive at 10, 5, and 2.5 mg doses groups [450]. doses have more or less disap- [358]. 1968 Epidemiological studies showed a peared. Microgynon® is still on 1959 Searle intended to add contracep- high rate of pulmonary embolism the market even today, more than tion as an approved indication for in the UK linked to the use of oral 35 years after its introduction and 10, 5, and 2.5 mg doses of Eno- contraceptives [340]. The evalua- used by hundreds of millions of vid™. The FDA refused the appli- tion of transcripts of 499 death cer- women worldwide. It is consid- cation until Searle agreed to with- tificates relating to women aged ered the standard product for con- draw the lower dosage forms from 20–44 who died in England, traception and was included in the the application [450, 719]. Wales, and Northern dur- WHO Model List of Essential 1960 The FDA announced the approval ing 1966 (pulmonary embolism Medicines. of Enovid 10 mg™ for contracep- [n = 77], coronary thrombosis [n = Lowering the EE dosage per tab- tive use. By this time Enovid 10 205], cerebral thrombosis [n = 27]) let from 50 to 30–35 µg led to a mg had been in general use for showed a strong correlation to the reduction of myocardial infarc- three years. In a conservative esti- use of the oral contraceptives tion, stroke and deep vein throm- mate, at least half a million women Enavid™/Enovid™. bosis (DVT).

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1992 The first large-scale study includ- – The meta-analysis by Gallo did not – Contraceptive efficacy is very good ing more than 60.000 women in focus on the severe adverse events and comparable to that of combina- Germany provided data about the like DVT. Theoretically the reduction tion OCs. prevalence of cardiovascular dis- of the EE content to 20 µg could lead – The intake scheme is also similar to ease in the family history of OC to a reduction of DVT risk. the combination preparations but due users [569]. – For the ultra-low dose class of COC, to continuous intake, fewer intake er- non-contraceptive benefits including rors and problems with medication 20 µg ethinyl estradiol containing pills protection against endometrial and adherence may occur compared to 1992 A further reduction of the EE dos- ovarian cancer must still be proven by conventional 21+7 COC. age from 30–35 to 20 µg EE per epidemiological trials. Indications tablet became possible and was ef- – Furthermore, additional data about Estrogen-free OCs are suitable for fective in preventing pregnancies. bone health (i.e. BMD, fracture etc.) women of all ages who desire quickly Lovelle, an ultra low dose OC con- are necessary. reversible oral contraceptives. In addi- taining 20 µg EE, was introduced tion, they are suitable for patients with by Organon. A Cochrane data- 15 µg ethinyl estradiol containing OCs specific indications [6] such as: base analysis of the contraceptive [501] effectiveness, side-effects and The amount of EE per tablet was re- – Cycle-dependent complaints: men- bleeding pattern under ultra-low- duced even further to 15 µg per day. Al- strual migraine, premenstrual syn- dose pills (20 µg) versus OCs with though these very low dose combina- drome (PMS), dysmenorrhea, hyper- > 20 µg EE/tablet was published by tions are theoretically better tolerated menorrhea Gallo et al. (2005) [200]. The re- by women with metabolic risk factors – Estrogen-dependent complaints: obe- port stated that women taking OCs [38], they appear to be less well toler- sity, tendency for edemas, uterine fi- with less estrogen tend to quit the ated in terms of bleeding pattern disrup- broids, and endometriosis studies early due to higher rates of tion and sex life compared with a 20 µg – disrupted bleeding patterns than EE containing pill or a vaginal ring de- – Risk factors or diseases representing women using OCs with a higher livering 15 µg of EE per day [570]. The contraindications for estrogen-pro- EE content. This review did not effect on bone mineral density of such gestin combination OCs show differences between the low dose EE treatment remains to be Clinical profile: estrogen containing OCs concern- determined. – It was recently demonstrated that the ing their contraceptive effective- Summary: 75 µg desogestrel-only pill (Cera- ness. – Lowering the EE dosage per tablet zette) could maintain ovulation inhi- 1996 A lower dosed monophasic prepa- from 30–35 to 15 µg may lead to a bition even after a 12 h delay in tablet ration containing 20 µg EE/100 µg further reduction of DVT, but studies intake [379]. However, regardless of levonorgestrel was developed and are lacking. the route of administration, the main introduced by Schering under the – Non–contraceptive benefits including drawback of progestin only contra- name Miranova® in 1998. In this protection against endometrial and ceptives is the high incidence of ir- COC product, the proportions of ovarian cancer must be proven by epi- regular leading to estrogen and progestin were main- demiological trials for this class of discontinuation rates of close to 25% tained, ensuring a balance between COC. [381] Breakthrough bleeding in POP the components. This low dose – Furthermore, new data about bone users can be related to incomplete preparation proved the concept (i.e. BMD, fracture etc.) health are suppression of ovarian activity or to a that COCs containing less than necessary. direct effect of progestins on the en- 30 µg EE can achieve reliable con- dometrium. traceptive efficacy and acceptable 3.2.2. Monophasic Oral Contraceptives – The estrogen-free pill is well-toler- cycle control. Later on, this led to Without Ethinyl Estradiol ated. Due to the partial androgenic ac- further successful developments Desogestrel-only pill (Cerazette®, MSD tivity of desogestrel, this OC it not by Bayer HealthCare (formerly then Organon) suitable for women with seborrhoea, Schering), such as OCs containing or acne. Clinical practice has shown drospirenone (Yasminelle® and 1999 Introduction of an estrogen-free that they should not be used in case of YAZ ®). oral contraceptive with desogestrel recurrent menstrual disorders [6, 7]. (Cerazette from MSD then Orga- – Similar to other progestin prepara- Summary: non). tions with continuous intake, irregu- – Lowering the EE dosage per tablet lar bleeding is not predictable. Some from 30–35 to 20 µg per tablet in a Rationale: women experience regular weak 21+7 regimen led to comparable con- – A progestin-only pill with a progestin bleeding, while others suffer from in- traceptive effectiveness but to often dose above the ovulation inhibition termediate bleeding, breakthrough inadequate bleeding control. Regi- dosage achieves complete ovulation bleeding or amenorrhea. mens with a shorter hormonal with- inhibition. In addition it impairs fer- drawal interval (24+4) showed char- tility based on three peripheral fac- Safety profile: acteristics which differed less from tors: the Fallopian tube, the endo- – Even when the desogestrel estrogen- OCs containing 30–35 µg EE. metrium and the cervix. free pill is taken for several years, the

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endogenous estradiol production is 10 primordial follicles. As estrogen (2008) [462] demonstrated an overall not suppressed to such an extent that and inhibin-B levels increase and sup- ovulation incidence of 2.0% (1.1– it would favor osteoporosis. press FSH, only the follicle with the 3.3) for COCs containing 30–35 μg highest expression of FSH receptors EE, 1.1% (0.60–2.0) for 15–20 μg Summary: survives this low-FSH environment to EE, 4.6% (2.8–6.9) for phasic COCs, – Estrogen-free contraceptives with become the leading follicle. 1.25% (0.03–6.8) for a desogestrel– ovulation inhibition are a good choice During the hormone–free interval of only pill and 42.6% (33.4–52.2) for for hormonal contraception. an OC regimen, FSH begins to in- traditional progestin-only pills. – These OCs can be used when estro- crease in line with the physiological gens are contraindicated or not well state of a normal menstrual cycle. – Contraceptive efficacy was not im- tolerated, and in breastfeeding women. When very-low-dose estrogen/pro- proved by a low EE dose drospiren- – Lowering the EE dosage per tablet gestin OCs are taken, this rebound one 24+4 regimen. from 30–35 to 0 µg led to a further occurs rapidly and follicles begin to reduction of DVT [422]. develop. When follicles develop – the – Estrogen withdrawal symptoms: – The safety margin for “missed pills” critical size might be as small as Sulak et al. (2000) [633] performed a is 12 hours. 14 mm – escape ovulation may occur study including 262 women (26 with – Regardless of the route of administra- despite the fact that active OC pills no previous OC use, 43 prior users, tion, the main drawback of progestin are taken and FSH is suppressed [33]. and 193 current users) who kept daily only contraceptives is the high in- – According to Sulak and Liu 2008 records of hormone-related symp- cidence of irregular vaginal bleeding 632], up to 30% of women may ovu- toms. Women with no prior OC use leading to high discontinuation rates. late on OCs when the hormone-free and prior users restarting were pooled – Another solution to the tablet intake interval is extended [33]. Studies have for analysis as new-start OC users. delay problem might be new non– shown that the dramatic rise in FSH Current users had patterns of symp- user dependent administration routes, occurs around the fourth day of a toms that were more frequent during such as implants. They (Norplant®, 7-day hormone-free intervall, fol- hormone-free intervals than during Jadelle® and Implanon®) contain lowed rapidly by the rise in 17-beta the 3 active-pill weeks. These inclu- levonorgestel or . They estradiol from the ovarian follicles ded pelvic pain (70% versus 21%, are safe and highly effective [205, [634, 713]. Even in women using a 30 p < 0.001), headaches (70% versus 458]. µg pill there may be a 500% increase 53%, p < 0.001), use of pain medica- in estradiol, from 10 pg/ml to almost tion (69% vs 43%, p < 0.001), bloat- 3.2.3. Monophasic OCs with Ethinyl- 60 pg/ml [713]. ing or swelling (58% versus 19%, estradiol and Different Regimens p < 0.001), and breast tenderness 3.2.3.1. Shortening the pill-free interval – Reduced placebo regimen by short- (38% vs 16%, p < 0.001). Similar pat- in 28 days regimens ening the pill free interval [632]: terns were seen in new-start OC users Rationale: Starting in 1998 with the approval of after the first cycle. Among new-start – In 2008, there was a renaissance of a Mircette, a number of modifications OC users, menstrual flow patterns, shorter placebo regimen; existing pat- to the 21/7 regimen have been made. headache, bloating or swelling, and ents had prevented the “new” discov- Mircette™ is a regimen including 21 breast-tenderness symptoms de- ery and development of OCs with a days of 20 µg EE and 0.15 mg creased during the three cycles to ap- shorter hormone-free interval. desogestrel, 2 placebo days, and 5 proach the levels of current users. Due to the high doses in the first- and days of 10 µg EE pills. By adding It is possible that the adverse effects second generation OCs and the 21/7 10 µg EE in the last 5 placebo pills a in the pill free interval may be spe- regimen, the hormone levels declined stronger ovarian suppression and less cific to progestins; i.e. the anti- in the week without pill intake. follicular development was achieved mineralocorticoid action of drospi- – For low-dose OCs and a 7-day hor- [372]. This led to a bleeding profile renone counterbalancing the in- mone–free interval (HFI), Sulak and comparable to OCs with 30 µg EE creased aldosterone is not opposed Liu (2008) [632] described a high in- [554, 651]. The use of a very low- during the pill-free interval. This cidence of hormonal withdrawal dose estrogen instead of the placebo could lead to fluid retention through symptoms, unscheduled bleeding (i.e. suppresses the pituitary, prevents “re- increased aldosterone and corre- breakthrough bleeding or spotting), bound” FSH rise and attenuates the sponding symptoms. and, finally, a high rate of break- rise of inhibin B, so that new follicles through ovulations. do not begin to develop [540]. This Further comments: – The reason for these symptoms is the prevents a situation where increased –The OCs that have been approved interaction of contraceptive steroids endogenous production interferes since 2003 and feature modifications with follicular development during with the next cycle and causes break- of the 21/7 regimen are mainly the menstrual cycle [632]. In the nor- through bleeding [554, 680]. Seasonale™ (84+7 placebos), Seaso- mal menstrual cycle, the pituitary se- nique™ (84+7 low EE pills), Low cretion of follicle-stimulating hor- Discussion of Sulak’s opinion: Seasonique™ (84+7) and Yaz™ mone (FSH) increases dramatically – Breakthrough ovulations may not be (24+4 regimen). during the first 2 days of the cycle, as frequent as generally assumed: In a – Hormone withdrawal symptoms in triggering the development of up to literature review, Milson and Korver the pill-free interval depend on the

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dosages of steroids used and mainly regimens should be offered, and – Bleeding pattern: At 6 months, sig- on the half-life of the progestins. many (81%) had prescribed such nificantly less breakthrough bleeding Progestins such as nomegestrol ac- regimens before. A small number of was noted with the 24/4 versus the etate (50 hours), drospirenone (40 respondents (12%) viewed monthly 21/7 regimen (mean number of days hours), cyproterone acetate (30 hours), withdrawal bleeding resulting from a 0.95 vs. 1.63, p = 0.005). In addition, chlormadinone acetate (36–39 hours) traditional 21/7 regimen as “neces- the 24/4 group had a mean with- have a longer half-life. In the case of sary and having health benefits.” Ob- drawal bleeding duration of 2.66 days these substances, declining steroid stetricians and gynecologists were compared with 3.88 days in the 21/7 concentrations are still detectable af- more likely (94%) to offer extended- group (p < 0.001). ter the withdrawal of the active tablets and continuous-cycle regimens than in the pill-free intervall. The half-life prescribers in other specialties (81%). Summary: of other progestins is shorter: levo- – The 24+4 regimen based on norethin- norgestrel (15 hours), gestodene (12 Norethindrone/EE 24+4 pill (brand drone and low dose estrogen provides hours), desogestrel (12 hours), dieno- name: Loestrin 24 Fe) a good contraceptive efficacy and gest (8–10 hours) [454] and nor- Product: Loestrin 24 Fe™ (EE 20 µg– bleeding pattern. ethisterone (7 hours). norethindrone 1 mg (Loestrin 24 Fe; – The discontinuation rate due to side – A lot of excellent studies demonstrate Warner Chilcott, Rockaway, NJ) pro- effects was as low as 6,2%. that a shortening of the pill-free inter- vides a dosage regimen consisting of 24 – Using ferrous fumarate in the 4 place- val led to a better suppression of folli- tablets with 1 mg norethindrone acetate bos as iron supplementation is an ad- cle recruitment but clinical trials pre- and 20 µg EE and 4 brown ferrous fuma- ditional feature of this OC. A product pared to obtain approval for COC rate (placebo) tablets. without iron supplementation is avail- with the 24+4 regimen based on able, or the placebo tablets can be drospirenone [32, 179] and chlor- – Side effects: The most common ad- skipped. madinone acetate [64] did not show a verse events reported by 2–6% of the better contraceptive efficacy or bleed- 743 women using Loestrin 24 Fe™ Drospirenone/EE 24+4 regimen ing control compared to traditional were in order of decreasing inci- (brand name: YAZ™) 20 µg EE-containing combined oral dence: headache, vaginal candidosis, 2006 The first 24+4 regime with dros- contraceptives. upper respiratory infection, nausea, pirenone called YAZ™ and con- – The longer annual exposure time to menstrual cramps, breast tenderness, taining 20 µg EE and 3 mg drospi- steroids must be carefully monitored sinusitis, vaginitis (bacterial), abnor- renone was introduced in the US in long term trials with these formula- mal cervical smear, acne, urinary tract 2006. It has been on the German tions. infection, mood swings, weight gain, market since 2009. For the US, it – Patient and health care provider at- vomiting, and metrorrhagia. Among has been approved by the FDA for titudes [315]: Most women and the 743 women using Loestrin 24 3 indications; in Europe it has only health care providers are considering Fe™, 46 women (6.2%) stopped tak- been approved for contraception. options other than the traditional oral ing the drug because of an adverse contraceptives that result in a 28-day event. Adverse events occurring in 3 or Contraception (rx-list) [322] cycle and monthly withdrawal bleed- more subjects leading to discontinua- – Indication: YAZ™ is indicated for the ing. International studies have dem- tion of treatment were, in decreasing prevention of pregnancy in women onstrated that each cultural context order: abnormal bleeding (0.9%), who elect to use an oral contraceptive. has its own beliefs [206, 710]. Health nausea (0.8%), menstrual cramps – Contraceptive efficacy (US trials) care professionals providing care to (0.4%), increased blood pressure [32]: The pregnancy rate (Pearl an ethnically diverse population need (0.4%), and irregular bleeding (0.4%). Index)(PI) was 1.41 per 100 woman- to realize the influence of culture on – Contraceptive efficacy: A 6–month, years of use based on 12 pregnancies attitudes regarding reproductive open–label, randomized, active–con- that occurred after the onset of treat- health. trolled study was conducted in the ment and within 14 days after the last One survey of U.S. women demon- United States to determine the effi- dose of YAZ™ in women 35 years of strated that 59% would be interested cacy of this new 24/4 regimen [476]. age or younger during cycles in which in menstruating less often; 56% In addition, the frequency of break- no other form of contraception was would be interested in menstruating through bleeding under the 24/4 regi- used. every 3 months or not at all, and 33% men was compared with that of a tra- According to Fenton et al. (2007) would consider using a contraceptive ditional 21/7 regimen. Both prepara- [179]: For the US trial, the PI adjusted method that would induce amenor- tions contained EE 20 µg/norethin- for noncompliance was 0.72; rhea [20]. A more recent survey ex- drone 1 mg. Healthy women of child- In the European trial [250] the uncor- amined the attitudes and prescribing bearing age were included and rected PI was 0.49 [179]. patterns of U.S. health care providers randomized. After 6 months of treat- The cumulative pregnancy rates were (including physicians, physicians’ as- ment, the Pearl Index was 1.82 in the 1.26% [179] and 0.5% in the interna- sistants, and nurse practitioners) re- 24/4 group versus 2.98 in the 21/7 tional and EU trials [179]. garding extended and continuous-cy- group. The study was not powered to – Oral Contraceptive Clinical Trial in cle oral contraceptives [631]. Most detect differences in contraceptive ef- the US [32]: In the primary contra- (87%) respondents thought that these ficacy between the two groups. ceptive efficacy study of YAZ (3 mg

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DRSP/20 µg EE) with a duration of effect of YAZ™ using the Daily trolled studies, 889 subjects, aged 14 up to 1 year, 1,027 subjects were en- Record of Severity of Problems scale, to 45 years, with moderate acne re- rolled and completed 11,480 28-day a patient-rated instrument that as- ceived YAZ™ or placebo for six 28 cycles. The age range was 17 to 36 sesses the symptoms that constitute day cycles. The primary efficacy end- years. The racial demographics were: the DSM-IV diagnostic criteria. The points were the percent change in in- 88 % Caucasian, 4.6% Hispanic, primary study was a parallel group flammatory lesions, non-inflamma- 4.3% Black, 1.2% Asian, and 2.1% design that included 384 evaluable re- tory lesions, total lesions, and the per- other. Women with a BMI greater productive-aged women with PMDD centage of subjects with a “clear” or than 35 were excluded from the trial. who were randomly assigned to re- “almost clear” rating on the Investi- ceive YAZ or placebo treatment for 3 gator’s Static Global Assessment Premenstrual dysphoric disorder menstrual cycles. The supportive (ISGA) scale on day 15 of cycle 6 (PMDD) [322]: study, a crossover design, was termi- showing according to the ISGA a total – Indication in the US: YAZ™ is also nated prematurely prior to achieving success rate for the reduction (Yaz indicated for the treatment of symp- recruitment goals due to enrolment versus placebo) in the first trial of toms of premenstrual dysphoric dis- difficulties. A total of 64 women of 15% (35/228) versus 4% (10/230) (35 order (PMDD) in women who choose reproductive age with PMDD were (15%), and in the second trial of 21% to use an oral contraceptive as their treated initially with YAZ™ or pla- (46/218) versus 9% (19/213). Data method of contraception. cebo for up to 3 cycles followed by a given for non-inflammatory lesions – Effectiveness over time: The effec- washout cycle and then crossed over lesions have been reported [322]. tiveness of YAZ™ for PMDD when to the alternate medication for 3 cy- used for more than three menstrual cles. Precautions [322]: cycles has not been evaluated. Efficacy was assessed in both studies In addition to precautions known for all – Definition of disease: The essential by the change from baseline during COC, there are progestin-specific pre- features of PMDD according to the treatment using a scoring system cautions for drospirenone, which has an Diagnostic and Statistical Manual – based on the first 21 items of the anti-mineralocorticoid activity 4th edition (DSM-IV) include mark- Daily Record of Severity of Prob- edly depressed mood, anxiety or ten- lems. Each of the 21 items was rated – including the potential for hyper- sion, affective instability, and persist- on a scale from 1 (not at all) to 6 (ex- kalemia in high-risk patients, compa- ent anger or irritability. Other features treme); thus a maximum score of 126 rable to a 25 mg dose of spironolac- include decreased interest in usual ac- was possible. In both trials, women tone. tivities, difficulty concentrating, lack who received YAZ™ had statistically – YAZ™ should not be used in patients of energy, change in appetite or sleep, significantly greater improvement in with conditions that predispose to and feeling out of control. Physical their Daily Record of Severity of hyperkalemia (i.e. renal insufficiency, symptoms associated with PMDD in- Problems scores. In the primary stu- hepatic dysfunction and adrenal in- clude breast tenderness, headache, dy, the average decrease (improve- sufficiency). joint and muscle pain, bloating and ment) from baseline was 37.5 points – Women receiving daily, long-term weight gain. In this disorder, these in women taking YAZ™, compared treatment for chronic conditions or symptoms occur regularly during the to 30 points in women taking pla- diseases with medications that may luteal phase and remit within a few cebo. increase serum potassium should days following onset of menses; the – Manufacturer’s note: To achieve have their serum potassium level disturbance markedly interferes with maximum contraceptive and PMDD checked during the first treatment cy- work or school, or with usual social effectiveness, the pill YAZ™ must be cle. activities and relationships with oth- taken exactly as directed at intervals – Medications that may increase serum ers. Diagnosis is made by healthcare not exceeding 24 hours potassium include ACE inhibitors, providers according to DSM-IV crite- – Limitations: YAZ™ has not been angiotensin-II receptor antagonists, ria, with symptoms assessed prospec- evaluated for the treatment of the pre- potassium-sparing diuretics, potas- tively over at least two menstrual cy- menstrual syndrome (PMS). sium supplementation, heparin, al- cles. When making the diagnosis, dosterone antagonists, and NSAIDS. care should be taken to rule out other Acne vulgaris [322]: cyclical mood disorders. – Indication in the US: YAZ™ is indi- Summary [179]: – Clinical trials: Premenstrual Dys- cated for the treatment of moderate – 24+4 regime: Novel low dose oral phoric Disorder Clinical Trials: acne vulgaris in women at least 14 hormonal contraceptive containing Two multicenter, double-blind, ran- years of age, who have no known 20 µg EE combined with the innova- domized, placebo-controlled studies contraindications to oral contracep- tive progestin drospirenone (3mg) in were conducted to evaluate the effec- tive therapy and have achieved me- a regimen of 24 days of active tablets tiveness of YAZ in treating the symp- narche. YAZ™ should be used for the followed by a short hormone free in- toms of PMDD. Women aged 18–42 treatment of acne only if the patient terval (4 days; 24/4 regimen)(brand who met DSM-IV criteria for PMDD desires an oral contraceptive for name: YAZ™). confirmed by prospective daily rat- birth control. – Drospirenone, unlike other synthetic ings of their symptoms were enrolled. – Clinical trials: In 2 multicenter, dou- progestogens used in COCs, is a 17α- Both studies measured the treatment ble blind, randomized, placebo-con- spirolactone derivative with anti-

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androgenic and antimineralocorticoid patic dysfunction and adrenal insuffi- lawsuit against Watson in the United properties (leading to a significant in- ciency, or those receiving other medi- States District Court for the District crease in serum aldosterone). cations that may increase serum po- of New Jersey involving Watson’s – US approval: Yaz™ has been ap- tassium) [179]. Quasense™ product, which is a ge- proved in the US for the prevention of – Continuous use: new clinical trials neric equivalent of Teva’s Seasonale™. pregnancy in women, for the treat- are investigating the possibility of an Under the terms of the settlement ment of the symptoms of premen- extended use of Yaz under the name agreement, Teva has granted Watson a strual dysphoric disorder (PMDD) of Yaz flex™ similar to the principle fully paid-up license to the U.S. pat- and for the treatment of moderate of Lybrel™ using levonorgestrel. ents covering Seasonale™, and Watson acne vulgaris in women who wish to (Watson Pharmaceuticals, Inc. has use an oral contraceptive for contra- 3.2.2.2. Continuous Daily Regimen for announced that its subsidiary, Watson ception. 3 Months Laboratories, Inc. will continue mar- – European approval: only for contra- Three different low dose combined oral keting its generic equivalent product ception, because in Europe rando- contraceptive pills with different regi- Quasense™ (levonorgestrel and EE mized control trials for drug approval mens are currently on the US market. tablets USP, 0.15 mg/0.03 mg). Watson (i.e. acne and PMDD) must be con- ● Seasonale™ [574] (Generics: further admits that the licensed pat- ducted against a competitor and not a Quasense™, Jolessa™ [305]. It was ents are valid and enforceable. Barr placebo. first developed by Barr Pharmaceuti- Pharmaceuticals also produces the – Contraceptive efficacy: The contra- cals and approved in 2003 by the FDA same medicine as a generic called ceptive efficacy is different between [177]. It is now produced by Teva Jolessa™. US and European trials, which has Women’s Health, containing 30 µg of also been shown for other contracep- EE and 150 µg of levonorgestrel in ● Seasonique™ 333], [574] (Generic: tive efficacy studies. The adjusted each active pill for 12 weeks (84 d), Lynoral®): To counteract the un- Pearl Index of 1.26 in the interna- followed by 1 week (7 d) of placebo planned bleeding, a newer version of tional and 0.5 in the European trials is tablets. Seasonale™ gives the benefit Seasonale (Seasonique) was devel- in the range expected for low dose of less frequent periods (from thirteen oped by Duramed Pharmaceuticals, oral contraceptives [179]. per year to four per year) with the po- now Teva Women‘s Health. Sea- – PMDD and acne vulgaris: The same tential drawback of breakthrough sonique™ has active pills and pack- treatment regimen over three treat- bleeding. Although Seasonale™ us- aging identical to Seasonale™, but ment cycles also improved the emo- ers have fewer scheduled menstrual replaces the placebo week with a low- tional and physical symptoms associ- cycles, data from clinical trials show dosage week of estrogen (84 active ated with PMDD significantly as well that, especially in the first few cycles pills with 30 µg of EE and 150 µg of as alleviating moderate acne vulgaris of use, many women had more un- levonorgestrel followed by 7 more ac- over six treatment cycles in double planned bleeding and spotting be- tive pills with 10 µg EE) instead of the blind trials [179]. tween the expected menstrual periods traditional placebo). Teva [289] ac- – Side effects: Due to the fact that OC than women taking a conventional quired Seasonique™, a newer version products containing drospirenone are 28–day cycle of an oral contraceptive of the now-generic Seasonale™, in market leaders, even the reporting of [16]. the 2008 purchase of Barr Laborato- side effects is more frequent than for Method failure: A parallel, rando- ries. Teva Pharmaceutical Industries other brands with other progestins. mized, multicenter open-label, 1-year Ltd., the world’s biggest generic-drug It was generally well tolerated, with study of the OC Seasonale™ (30 µg maker, won a court ruling that up- most adverse events typical of those EE/150 µg levonorgestrel (LNG) (n = holds the validity of the U.S. patent experienced with other COCs and 397), and Nordette-28™ (30 µg EE/ on its Seasonique™ birth-control tab- most likely to occur in the first few 150 µg LNG) (n = 195) in sexually let which will expire in 2024. The two cycles [179]. active, adult women (18–40 years) of main advantages of replacing the pla- The rate of venous thromboembolism childbearing potential led to method cebo week with a week of low-dose corresponds to the rates of products failure (Pearl Index) of 0.60 for estrogen are a reduced incidence of containing levonorgestrel, dienogest, Seasonale™ and 1.79 for Nordette™ unplanned bleeding and spotting and chlormadinone acetate, norethiste- [15]. fewer or no symptoms (e.g., cramps, rone and lynestrenol and seems to be According to data published in the rx- bloating, headaches) for women who lower than for gestodene, desogestrel list in a 1-year controlled clinical trial are sensitive to the placebo week hor- or cyproterone acetate. New ongoing 4 pregnancies occurred in women mone fluctuations (in particular, low studies are needed to provide further aged 18–35 during 809 completed estrogen). A study of 1000 sexually proof of this. See Table 3 [539] 91-day cycles of Seasonale™ during active adult women (aged 18–40) – Precautions: As drospirenone is a which no backup contraception was who used Seasonique™ for one year spironolactone analogue with anti- utilized. This represents an overall found that, for cycles 2–4, the median mineralocorticoid activity, it has the use-efficacy (typical user efficacy) number of bleeding days on a per-pa- potential to induce hyperkalemia in pregnancy rate of 1.98 per 100 tient month basis was minimal (<1 d) high risk patients (those with condi- woman-years of use [320]. [14]. tions that predispose them to hyper- ● Quasense™ [316]: On December 13, Method failure: In a multicenter, kalemia, i.e. renal insufficiency, he- 2007, Teva filed a patent infringement open–label, 1 year study the method

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failure of Seasonique™ (30 µg EE/ Summary: Nevertheless the high rate of intermen- 150 µg levonorgestrel for 84 days fol- – Three different 91-days regimens strual bleedings and a higher Pearl Index lowed by EE 10 µg for 7 days) was with combined oral contraceptives when compared to combined oral con- 0,78 (Pearl Index) and 0,64% (life have been developed with the aim of traceptives meant that European ap- table analysis) [14]. reducing menstrual bleeding to 4 proval of Lybrel™ was refused. Adverse reactions leading to study times a year. discontinuation: 16.3% of the women – The contraceptive efficacy (Pearl In- Summary: dropped out of the clinical trial due to dex) ranges between: 1.98 for Seaso- ● Lybrel™ is a new low dose combined an adverse reaction; the most common nale™, 1.34 for Seasonique™ and oral contraceptive with a 365-day adverse reactions (≥ 1% of women) 2,74 for LoSeasonique™. regimen. leading to discontinuation were ir- – The products Seasonale™, Seaso- ● The only pill for an “extended cycle” regular and/or heavy uterine bleeding nique™ and LoSeasonique™ are of up to one year approved with clini- (5.9%), weight gain (2.4%), mood only available in the US. cal data about efficacy and safety. changes (1.5%), and acne (1.0%) – In many European countries, ex- ● High intermenstrual bleeding meant [321]. tended cycles are recommended to that the product was not approved in Risk profile: The risk profile of us- OC users for the “off-label” use of Europe. ing Seasonale™ is similar to that of combined oral contraceptives, vagi- ● No long-term safety data are available other conventional combined oral nal rings or hormonal patches. for long term use and for a higher contraceptives and includes an in- – An alternative is the use of a 365-day steroid exposure than traditional creased risk of blood clots, heart at- regimen Lybrel™ (containing low- 21+7 combined OCs. tack, and stroke. The labeling also dose EE (15 µg) and levonorgestrel carries the warning that cigarette (90 µg)). YAZ Flex™ smoking increases the risk of serious Ongoing studies are investigating the adverse cardiovascular effects from 365 days regimen = continuous daily contraceptive efficacy, clinical tolerabil- the use of combination estrogen and regimen ity and control of the menstrual cycle progestin-containing contraceptives. Lybrel™ (generic: Anya™) achieved by a product called Yaz Flex™ The study cited for Seasonique does – Rationale: continuous administra- developed by Bayer HealthCare. not report any unexpected adverse tion of low-dose progestin and EE events or thromboembolic events; suppresses follicular maturation, ovu- Extended regimen with combined oral the risk profile is the same as lation and menstrual bleedings. This contraceptives based on “off label” Seasonale. is a continuation of the idea of the use outside the US Seasonale inventors or the extended If the pill formulation is monophasic, it ● LoSeasonique™ [332, 574] has been cycle with classic combined oral con- is possible to skip withdrawal bleeding produced by Teva Women‘s Health traceptives. and still remain protected against con- (previously Duramed Pharmaceuti- – FDA approval [740]: In 2007 the ception by skipping the placebo pills and cals) since 2009. LoSeasonique™ U.S. Food and Drug Administration starting directly with the next pack. At- consists of 84 orange tablets contain- (FDA) approved Lybrel™ (90 µg tempting this with bi- or tri-phasic pill ing 0.1 mg levonorgestrel and 20 µg levonorgestrel/20 µg EE tablets) formulations carries an increased risk of EE and 7 yellow tablets containing (Pfizer then Wyeth-Ayerst) for a low breakthrough bleeding and may be un- 10 µg EE. dose, continuous, non-cyclic combi- desirable. It will not, however, increase The risk profile is similar to Sea- nation oral contraceptive designed to the risk of getting pregnant. An increas- sonale™ and Seasonique™; however, be taken continuously with no place- ing number of women are using OCs as a the risk of unplanned breakthrough bos and withdrawal bleeding [176]. long cycle (3, 6 or more blisters of a con- bleeding is increased. In a clinical Lybrel® is currently available at phar- tinuous combined OC without an OC trial over a 12-month period, 209 of macies in the US on prescription only. free interval). the 2185 participants (9.6%) discon- This drug is marketed under the name tinued LoSeasonique™; at least some of Anya or Lybrel™. Studies have – Rationale: continuous administra- of them due to bleeding and/or spot- shown that after seven months, 71% tion of low dose progestin and EE ting. The breakthrough bleeding re- of users no longer had any break- through the extended use of classic mained consistent over time, averag- through bleeding, the most common combined oral contraceptives shows a ing 2–3 days of bleeding and/or spot- side effect of going on active pills for good contraceptive efficacy and free- ting per 91-day cycle. The break- longer periods of time without breaks dom from menstrual bleeding in most through bleeding eventually decreased [705]. The product went on the mar- users. over successive 91-day cycles. ket in 2008, and Wyeth invested more – Clinical profile: In all COCs using an into advertising this drug than any extended-cycle, breakthrough bleed- In a multicenter, open-label, single other medicine before [274]. ing is the most common side effect, treatment phase 3 study (n=1249 – Clinical profile: In clinical trials (n = although it tends to decrease over completed the study) the method fail- 2,134) performed by the Conrad Pro- time [16]. In a 12-month study of a ure of LoSeasonique™ was 2,74 gram (US) (2006), a Pearl Index of continuous COC regimens, 59% of (95% confidence interval 1,92–3,78) 1,26 has been reported with absence women experienced no bleeding in (Pearl Index) [386]. of bleeding in 79% of cases [24]. months six through 12 and 79% of

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women experienced no bleeding in bleedings and the intention of the Rationale: biphasic pills were intro- month 12 [24]. user relative to the duration of use duced to the market in 1963 with the in- – Risk profile: Extended or continuous ● No safety data are available for tention to offer OCs with a better control use of COCs or other combined hor- long-term use and for a higher ster- of the bleeding pattern and the side ef- monal contraceptives carries the same oid exposure than traditional 21+7 fect profile. risk of side effects and medical risks combined OCs Biphasic regimen: Biphasic birth con- as traditional COC use. ● Women must be informed about trol pills alter the level of hormones once – Safety data: There are no available the “off label” use. during the menstrual cycle. There are data at this time concerning the long- ● Furthermore, they have to be in- two types on the market: term effects of menstrual suppression formed about the management of – Step-up-regimen: One type of OC on a woman’s overall health. There is breakthrough bleedings and with- delivers the same amount of estrogen concern in the medical field that in- drawal bleedings. If a regular con- each day, but the level of progestin is creasing the amount of hormones trol bleeding occurs, the extended increased about halfway through the typically taken by a woman may have cycle must be stopped, and a new cycle. Although the estrogen level re- an on her long-term extended cycle can be started after mains the same, during the first half health, but there is no data to confirm a pill-free interval. of the cycle, the progestin/estrogen or disprove this. ● Nethertheless there is great experi- ratio is lower to allow the endo- – Cochrane: In a Cochrane analysis by ence in Germany with extended metrium to thicken as it normally Edelman et al. 2005 164] oral con- cycles, a method highly accepted does. During the second half of the traceptives taken continuously for by women and doctors. Use of this cycle, the progestin/estrogen ratio is more than 28 days compare favorably regimen in Germany is “off-label” higher to allow for the normal shed- to traditional cyclic oral contracep- and the women must be informed ding of the lining of the uterus. The tives. Six randomized controlled trials accordingly. progestin concentration in the first 7 met the inclusion criteria. Study find- ● According to a German study by to 10 days is different from the level ings were similar between 28-day and the Federal Centre for Health in the next 11 to 14 pills. The last 7 extended cycles in regard to contra- Education (BZgA)[68], 42% of tablets (if included) are placebo pills ceptive efficacy (i.e., pregnancy rates) all German women prefer regular and contain no hormone. and safety profiles. When compliance menstrual bleedings. – Two-phase-regimen: The other was reported, no difference between ● For further information, see types deliver different amounts of 28-day and extended cycles was (http://en.wikipedia.org/wiki/ EE and progestin in a biphasic fash- found. Participants reported high sat- Extended_cycle_combined_hormo- , e.g. Biviol® (German brand isfaction with both dosing regimens, nal_contraceptive) [272] name/MSD): 7 days: 250 µg deso- but this was not an outcome univer- gestrel, 40 µg EE; 15 days: 125 µg sally studied. Overall discontinuation 3.3. Multiphasic Birth Control desogestrel, 30 µg EE and discontinuation for bleeding Pills [268] OC-market in Germany: problems were not uniformly higher Multiphasic oral contraceptives were de- – Desogestrel (7 days 40 µg EE & in either group in most studies. The veloped in the 1980s. Phasic birth control 250 µg desogestrel/15 days 30 µg EE few studies that reported menstrual pills contain varied amounts of hormones & 125 µg desogestrel) symptoms found that the extended designed to be taken at specific times – Levonorgestrel (11 days 50 µg EE & cycle group fared better in terms of throughout the course of each pill pack. 50 µg levonorgestrel/10 days 50 µg headaches, genital irritation, tired- These pills were developed to help lessen EE & 125 µg levonorgestrel) ness, bloating, and menstrual pain. the side effects of monophasic birth con- – Chlormadinone acetate (11 days Five out of the six studies found that trol pills. When compared to monophasic 50 µg EE & 1 mg CMA/11 days 50 µg bleeding patterns were either equi- oral contraceptives, some phasic birth EE & 2 mg CMA) (Note: chlormadi- valent between groups or improved control pills tend to lower the total hor- none acetate is not available in the with continuous-dosing regimens. mone dosage a woman receives while us- US). Endometrial lining assessments by ul- ing each pill pack; they are also designed trasound were done in a small number to more naturally mimic the female Summary: of participants but all endometrial body’s natural menstrual cycle. – Modern biphasic pills on the mar- stripe measurements were less than ket in Germany: see above list. 5 mm. 3.3.1. Biphasic Oral Contraceptives – Modern biphasic pills on the mar- [268] ket in Germany: Desogestrel (7 days – Summary: 1963 Introduction of sequential (bipha- 40 µg EE & 250 µg desogestrel/15 ● Extended cycles can be achieved sic) oral contraception in the Uni- days 30 µg EE & 125 µg desogestrel), based on the “off label” use of any ted States; Sequilar® was intro- levonorgestrel (11 days 50 µg EE & brand of combined oral contracep- duced in Germany in 1964. 50 µg levonorgestrel/10 days 50 µg tive, also the combined vaginal 1968 Development of multiphasic pre- EE & 125 µg levonorgestrel), chlor- ring and the combined contracep- parations (estrogens and proge- madinone acetate (11 days 50 µg EE tive patch. stins in two dose levels; origin: & 1 mg CMA/11 days 50 µg EE & ● A flexible duration of use is possible Australia). First introduced in Ger- 2 mg CMA) (Note: chlormadinone and should be based on unexpected many in 1969. acetate not available in the US).

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– Cochrane analysis by van Vliet et or in order to pre- or postpone men- hormonal fluctuations that occur al. (2006) [676]: Biphasic versus struation; the regimen for “missed during the menstrual cycle. Triquilar monophasic oral contraceptives: in pills” is more difficult than for com- achieves excellent contraceptive ef- a Cochrane analysis, van Vliet et al. bined pills. No biphasic pills with ficacy, good cycle control and is well 2006a [675] did not find enough evi- modern are on the mar- tolerated. dence to determine if two-phase pills ket. The VTE risk of desogestrel-con- Triphasic regimen: worked any better than one–phase taining OCs is higher than for levo- – Due to different patents, various regi- types for birth control, bleeding pat- norgestrel. mens in terms of different length of terns, or staying on the pill. One trial the 3 phases and different dosage report had methodological problems 3.3.2. Triphasic Birth Control Pills [268] regimens have been developed. and lacked data on pregnancies. 1977 Development of the tricyclic pill – Triphasic oral contraceptives contain Therefore, one-phase pills are the bet- (combination pill for 84 consecu- 3 different doses of hormones in the 3 ter choice, since we have much more tive days; origin: Great Britain). weeks of active pills, so the hormone evidence for such pills and there is no combination changes approximately clear reason to use two-phase pills. 1977 Development of low dose triphasic every 7 days throughout the pill pack. (Comment: weak Cochrane analysis preparations (3-phase dosing of Depending on the brand, the amount due to lack of data). estrogens and progestins; origin: of estrogen may change as well as the Germany). First introduced in amount of progestin. In a single – Cochrane analysis by van Vliet et al Germany in 1979 and abroad in month’s supply, triphasic pills may (2011) [676]: Biphasic versus tri- 1980. have a gradual estrogen increase and/ phasic contraceptives: The authors or some pills may also increase the found only two trials that looked at 1979 Triquilar®: In 1979, Schering, dose of progestin. two-phase versus three-phase birth Berlin, (now Bayer HealthCare) control pills. The studies had meth- introduced the first triphasic COC, German OC market: odological defects, and not all meth- Triquilar® in an attempt to reduce – Norethisterone: 35 µg EE/0,5; 1 mg ods had been reported. Many women the overall hormone content. The norethisterone; 35 µg EE/0.5–1 mg dropped out of the studies, which af- doses of the estrogen and the pro- norethisterone fects what can be said about the re- gestin components were altered – Levonorgestrel: 30; 40 µg EE/50– sults. One study compared two types during the cycle. 125 µg; 30; 40 µg EE/50;125 µg levo- of two-phase pills with a three-phase norgestrel pill. The pills did not differ in any 1994 Introduction of the first third-gen- – Norgestimate: 35 µg EE/180; 250 µg major way, including the number of eration triphasic pill in Germany norgestimate; (US: OrthoNovum 7/7/ women who stopped using the pills (norgestimate; Pramino® from 7™) due to health problems. The other trial Cilag – and Tricyclen® in the US). – Desogestrel: 30 µg EE/50–150 µg compared a two-phase pill with two desogestrel different three-phase pills. The two- 2001 Introduction of a triphasic oral phase pill had worse bleeding pat- contraceptive with desogestrel Summary: terns than the three-phase pill with a (Novial® from Organon (now – Modern triphasic pills on the mar- different hormone (levonorgestrel). MSD) (7 days 35 µg EE & ket in Germany: see list above. In contrast, bleeding with the two- 0,05 mg desogestrel 0,05 mg, EE – Cochrane analysis by van Vliet et al phase pill was like that of the three- 0,035 mg; 7 days: 30 µg EE & (2011) [676]: see biphasic pills. phase pill with the same hormone 0,1 mg desogestrel 0,1 mg; 7 days: – Indications: patients with intermen- (norethindrone). For cycle control, 30 µg EE and 0,15 mg desogestrel) strual bleeding, i.e. mid-cycle bleed- the type of hormone may be more im- ing or therapy resistant bleeding portant than the phases. These trials Rationale: problems using combined oral con- did not provide enough evidence to – Triphasic pills offered the lowest traceptives. say if three-phase pills worked any amount of total EE and progestin per – Limitations: Triphasic pills cannot better than two-phase types for birth cycle compared to other OCs contain- be used for extended cycles (“off la- control, bleeding patterns, or staying ing 50 µg EE at the time of market in- bel”) or for pre- or postponing the on the pill. More research would be troduction in 1970. menstruation; the regimen for “mis- needed to show whether three-phase – At that time, further dose reduction sed pills” is more difficult compared pills are better than two-phase pills. seemed difficult without a negative to combined pills. No triphasic pills However, two-phase pills are not used effect on cycle control. Triquilar® with modern antiandrogens are on the enough to justify further research. contained EE 30 µg/LNG 50 μg on market – with the exception of nor- – Indications: patients with intermen- days 1–6, EE 40 µg/LNG 75 μg on gestimate (Tri-Cyclen™), which has strual bleeding, i.e. mid-cycle bleeding days 7–11, EE 30 µg/LNG 125 μg on an approval for acne in the US only – or therapy-resistant bleeding problems days 12–21. Due to the phasic for- but norgestimate is only a weak anti- using combined oral contraceptives. mulation, the total hormone content androgen. The VTE risk of desoges- – Limitations: biphasic pills cannot be was reduced by 40%. Moreover it trel-containing OCs is higher com- used for extended cycles (“off label”) was designed to better resemble the pared to levonorgestrel.

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 4. New Oral Contraceptive a lack of androgenic activity [382, days each. The second study was con- Regimens 492]. ducted in Europe (Germany, Austria and – Estradiol valerate (E2V) is promptly Spain) as a multicenter, open-label, sin-

4.1. Progestin-Only Pills with hydrolyzed to E2 after oral adminis- gle-arm contraceptive reliability study.

Ovulation Inhibition tration, and is identical to E2 in terms There were 1,377 healthy subjects be- To date, only one desogestrel (75 µg/ of and pharma- tween 18 and 50 years of age (mean age: day) pill inhibiting ovulation due to a cokinetics [659]. An OC containing 30.3 years) who were treated for 20 cy- progestin dosage above the ovulation in- estradiol valerate (E2V) and dienogest cles of 28 days each [318]. hibition level has been marketed by in a four-phasic 26+2 regimen has MSD. been the first OC on the market with a Clinical trial for the treatment of derivative of a natural estrogen pro- : The effi-

4.2. Ethinyl Estradiol-free Con- viding both a good contraceptive effi- cacy of E2V/DNG for the treatment of traceptives Using Estradiol or cacy and sufficient control of the heavy, prolonged and/or frequent men- Estradiol Esters menstrual bleeding pattern. strual bleeding without an organic cause Over the years, development in the field – Ovulation inhibition is achieved by a measured by the alkaline haematin of combined oral contraceptives (OCs) progestin dosage above the threshold method was investigated in two identi- has focused on improving their tolerabil- necessary for ovulation inhibition and cally designed double-blind, randomi- ity by reducing the dose of progestins estrogens are used to prevent a rela- zed, placebo-controlled trials in USA/ and ethinyl estradiol (EE), modifying tive estrogen deficiency and thereby [190] and Europe/Australia the dosing regimen and incorporating achieve a good cycle control. [350]. progestins with more favorable clinical –E2V/DNG utilizes dynamic dosing in profiles. a simple and continuous 1-pill-per- Adverse reactions leading to study dis- day format, which delivers an estro- continuation: 11.5% of the women Additional efforts to improve the accept- gen step-down, progestin step-up dropped out of the clinical trials due to ability of combined OCs included the regimen over 26 days of active treat- an adverse reaction; the most frequent replacement of EE with 17β-estradiol ment, 2 days of placebo. This regimen adverse reactions leading to discontinu-

(E2 ). was designed to ensure good cycle ation were metrorrhagia and irregular control by maintaining estrogen menstruation (1.9%), acne (1.2%), head- 4.2.1. Dienogest/Estradiol Valerate in a dominance in the early part of the cy- ache and migraine (1.0%), and weight Combined Oral Contraceptive cle and progestin dominance in the increase (0.7%). E2V/DNG has been available in multiple mid-to-late part of the cycle. It also countries in Europe since May 2009, and provides stable trough E2 levels over Common treatment-emergent adverse is also available outside of Europe and in the whole 28-day cycle, with low reactions (≥ 2%): headache (including the USA. variability in E2 levels over 24 hours migraines) (13.2%), metrorrhagia and [737]. (8.0%), breast On May 13, 2010, the FDA approved a pain, discomfort or tenderness (6.6%), new COC called Natazia™, manufac- Experience with clinical trials: nausea or vomiting (6.5%), acne (3.9%) tured by Bayer HealthCare Pharmaceuti- Because clinical trials are conducted un- and increased weight (2.8%). cals of Wayne, N.J., which is the first der widely varying conditions, adverse four-phase oral contraceptive to be mar- reaction rates observed in the clinical tri- Serious adverse reactions: deep vein keted in the United States containing als of a drug cannot be directly com- thrombosis, myocardial infarction, focal estradiol valerate and dienogest in a pared to rates in the clinical trials of an- nodular hyperplasia of the liver, ute- four-phasic 26+2 regimen [319]. other drug and may not reflect the rates rine leiomyoma, and ruptured ovarian observed in practice. cyst. Indications: Natazia™ is indicated for use by women to prevent pregnancy. The Contraception Studies: Summary: efficacy of Natazia in women with a Two multicenter phase 3 clinical trials – First OC with estradiol valerate in a body mass index (BMI) of > 30 kg/m² evaluated the safety and efficacy of four-phasic regimen. has not been evaluated [318]. Natazia™ for pregnancy prevention. – The 4-phasic combination allows for Both were non-comparative, open-labe- the use of estradiol valerate instead of Rationale: led, single-arm studies with a duration of EE for contraception and control of

– In several historic clinical trials, E2- up to 28 cycles. A total of 1,867 women the menstrual cycle and to provide containing OCs have been found to aged 18–50 were enrolled and took at stable and sufficient serum levels of provide effective contraception, but least one dose of Natazia. estradiol. their association with unsatisfactory The first study was conducted in North – Only one 4-phasic pill has been mar- bleeding profiles has largely prevented America (U.S. and Canada) as a multi- keted until now. The 4-phasic combi- them from being developed further center, open-label, single-arm, unin- nation of dienogest with estradiol [27, 135, 256]. tended pregnancy study. There were 490 valerate is the first oral contraceptive – Dienogest (DNG) is an established healthy subjects between 18 and 35 containing a derivative of a natural progestin with strong endometrial years of age (mean age: 25.1 years) who estrogen, which is converted in the effects, antiandrogenic properties and were treated for up to 28 cycles of 28 human body to the natural estrogen

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estradiol. Estradiol valerate is neces- liver is the exclusive site of 15α- and ovulated oocytes in the genital tract. All sary to overcome an estrogen defi- 16α- [441, 584, 585]. rats ovulated when treated with vehicle.

ciency during the cycle as a conse- After birth the neonatal liver rapidly The twice-daily dose of 0.3 mg/kg E4

quence of ovarian suppression by loses its capacity to synthesize E4. and the higher doses significantly inhib- dienogest to maintain constant levels was already detected at 9 weeks ited ovulation (p < 0.05) as did twice of estradiol and to support the good of pregnancy in maternal [240, daily administration of the comparator cycle control in terms of bleeding pat- 242]. During the second trimester of EE at the highest dose (0.03 mg/kg). By

tern. pregnancy high levels were found in ma- comparison of the ED50 the antiovulatory

– Clinical trial data show that E2V/ ternal plasma, with steadily rising con- potency of E4 was about 18 times less

DNG effectively inhibits ovulation centrations of unconjugated E4 to about thanEE. [135] and offers women an accept- 1 ng/ml (3 nmol/L) towards the end of In a single rising dose study in healthy able bleeding profile, with lighter pregnancy [99, 259]. So far the physi- postmenopausal women pharmacokinet-

bleeding and a significant reduction ological function of E4 has not been ics and pharmacodynamics of E4 were in the duration of withdrawal bleed- studied and is unknown. studied after administration of single

ing per cycle compared with EE/LNG The possible use of E4 as a marker for doses of 0.1, 1, 10 and 100 mg E4 [694]. [5]. fetal well-being has been studied quite To investigate the antigonadotrophic po-

– Significantly more patients per cycle extensively. However, due to the large tency of E4 the effect of E4 on the plasma had no withdrawal bleeding, although intra- and interindividual variation of levels of the gonadotrophins luteinising

only in a minority of cycles. maternal E4 plasma levels during preg- hormone (LH) and follicle stimulating – Treatment for heavy menstrual nancy this appeared not to be feasible hormone (FSH) was measured. A dose- bleeding: Together, the two interna- [241, 399, 400, 490, 664]. More details dependent inhibition of LH levels was

tional studies provide the first evi- on the history of E4 and data from studies observed. In addition in the 100 mg dose dence from rigorous randomized trials in the period from 1965 to 1984 have group (FSH was not measured in the that an oral contraceptive is an been summarized in two review papers other dose groups) a profound inhibition effective treatment for heavy men- [101, 259]. of FSH levels was observed lasting for

strual bleeding. Study results revealed In the last 7 years E4 has been studied 7 days.The effect of E4 on plasma LH a rapid effect of E2V/DNG, with a sig- extensively. High oral absorption and and FSH levels was also studied in a nificant reduction in menstrual blood with a 2–3 h elimination multiple rising dose study in early post-

loss seen from cycle two onwards. half-life in the rat have been established menopausal women with oral E4 doses

– Side-effect profile: No long-term [100]. In the human E4 showed a high of 2, 10, 20 and 40 mg/day administered

safety data are available demonstrat- and dose-proportional oral bioavailabi- for 28 days. A 2 mg/day oral E2-valerate ing the benefit in terms of a lower rate lity and a remarkably long terminal group served as control. In this study of cardiovascular disease. Prospec- elimination half-life of about 28 h [694]. both FSH and LH levels decreased dose

tive multicenter trials of the EURAS Estetrol has a moderate affinity for both dependently after administration of E4 type are ongoing. human ERα and ERβ receptors with a for 28 days. Suppression of LH and FSH α – Market overview: Only one modern 4–5-fold preference for the ER [693]. in the 2 mg E2-valerate group was ap-

four-phasic pill is on the market in In addition it was found that E4 binds proximately similar to the inhibitory ef-

Germany and the US. highly selectively to the estrogen re- fect of the 10 mg E4 dose group. Ovula- ceptors. tion inhibition was further investigated Estetrol for Contraception In rat and human hepatocytes the rate of in a phase IIA clinical trial in premeno-

According to Herjan Coelingh Bennink, E4 metabolism was studied and found to pausal women with proven ovulation in

Pantarhei Bioscience, The Netherlands, be slow [693]. In addition E4 did not in- the previous cycle. Estetrol was adminis- and Jean Michel Foidart, University of hibit any of the major drug-metabolizing tered alone in 2 different doses (10 or Liège, Belgium. enzymes CYP1A2, 20 mg/day) or in combination with either CYP2C9, CYP2C19, CYP2D6 and desogestrel (150 µg DSG) or progester-

Estetrol (E4) is a human steroid, pro- CYP3A4 at a high concentration of one (200 mg P4). All treatments were duced by the fetal liver during pregnancy 10 µM [693]. This is in contrast with the oral and for 28 days. Ovulation was in- only. This natural hormone was discov- effects of estradiol (E2) and ethinyl- hibited in all women in the E4/DSG ered in urine of pregnant women by estradiol (EE) on these enzymes. group, while in the 10 mg and 20 mg

Diczfalusy and coworkers in 1965 [221]. E4-only groups, ovulation was inhibited Based on its physical and chemical char- Contraceptives Studies in one third and two thirds of the cycles acteristics it was concluded that E4 In a preclinical model the effects of E4 on respectively. The E4/P4 group showed a is identical with 15α-hydroxyestriol ovulation inhibition were studied in cy- poor antiovulatory efficacy and an unac- (15α-OHE3) or estra-1, 3, 5(10)-triene- clic female rats. Animals (8 per group) ceptable bleeding pattern. All other α α α 3,15 -,16 -, 17 -tetrol [739]. Estetrol were treated twice daily with oral E4 E4 groups showed acceptable bleeding has the structure of an estrogenic steroid (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg), or oral patterns albeit for just one treatment cy- with four hydroxyl groups, which ex- EE (0.0003, 0.001, 0.003, 0.01 or 0.03 cle. A phase 2 program for the develop- plains the acronym E4. Estetrol is synthe- mg/kg) over the 4 days period of the ment of an E4 containing oral contracep- sized by the human fetal liver during estrous cycle [103]. The control group tive will be completed in 2011, including pregnancy and reaches the maternal cir- was given oral vehicle only. The primary E4 dose finding and progestogen selec- culation through the placenta. The fetal endpoint of this study was the number of tion.

110 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills

Summary: acid) system, explaining the lack of – NES has been shown to exert a high – Estetrol is a steroid synthesized ex- unwanted mood effects in users contraceptive activity when adminis- clusively by the human fetal liver dur- [553]. tered via different non-oral delivery ing pregnancy. After its discovery in routes such as vaginal rings, implants

1965, basic research on E4 was per- Contraception [602]: and transdermal systems. formed until about 1984. At that time – Preclinical studies in the rat have

E4 was considered to be a weak estro- demonstrated inhibition of ovulation Contraception [602]: gen and interest in this steroid disap- and anti-estrogenic activity in the – Oral contraceptives: The oral route peared. However, recently it has been uterus [718]. is not possible, because NES is not

shown that E4 has a high and dose-re- – The contraceptive potential of using absorbed following oral application. lated oral bioavailability in the rat TMG via a transdermal system has – Vaginal rings: A vaginal ring con- [100] and the human [694], does not been explored, but so far no clinical taining NES/EE releasing low doses bind to SHBG [225] and has a long trial has been published [435]. of NES (150 µg) and EE (15 µg) is un- elimination half-life in both rats [100] – Although TMG is a potent progestin dergoing development as a contracep- and humans [694], allowing its use as with good antiovulatory action, it has tive at the Population Council [35, an oral once-a-day drug. not been developed as a contraceptive 36]. At present, the ring is in its final – In well validated and predictive rat so far. stages of development. Second-gen-

models, E4 behaves as an estrogen eration vaginal rings, which include a in all tissues investigated, i.e. Summary: design delivering NES together with bone [100], vagina [238], myo- Trimegestone could be used as an oral E2, the natural estrogen, instead of metrium [238], endometrium [238] hormonal contraceptive. In 2007, the EE, are in the early developmental and brain (hot flush) [258] and ovula- German pharmaceutical company Grue- stage. The contraceptive potential of tion inhibition [238, 258], except for nenthal (http://www.prnewswire.co.uk/ NES delivered via the transdermal breast tumor tissue where this steroid cgi/news/relea se?id=203073) [317] an- route has also been studied. The first acts as an estrogen antagonist in the nounced its worldwide exclusive rights study testing NES as a transdermal

presence of E2 [102]. on trimegestone for the use in oral con- gel found it to be effective in sup- – Estetrol may be useful for a series of traception by Aventis Pharma, SA, pressing ovulation in a high percent- potential clinical applications includ- France, a subsidiary of Sanofi-Aventis. age of women [601]. ing hormone replacement therapy in Trimegestone is a metabolically neutral – NES-gel: In a 3-month multicenter women, especially for the treatment and naturally derived progesterone ago- study carried out among 150 cycling of vaginal atrophy and hot flushes, as nist, thus long-term acceptance female women, NES gel was applied trans- an estrogenic component in oral con- users is expected. Due to its favorable dermally in three different doses of traceptives as well as for the preven- metabolic safety profile trimegestone is 0.3, 0.6 and 1.2 mg. The level of ovu- tion and treatment of osteoporosis, already in use in hormone replacement lation suppression reached 53%, 64%

and E4 might even be suitable for the therapy. In this respect trimegestone is and 83% in the three dose groups, re- prevention or treatment of breast can- an ideal progestin to be used in hormo- spectively [134, 601]. cer. These potential applications will nal contraception. Based on these promising results, be further explored in clinical trials. higher doses of NES were combined

– Potential advantages of E4 over EE Nesterone with low doses of E2, and preliminary

and E2 include fewer subjective side Pharmacological profile: results indicate a high antiovulatory effects, less interaction with liver – Nesterone (NES) is a 19-norpro- efficacy. function, less venous thromboembo- gesterone derivative with a high pro- lism and a lower incidence of cardio- gestational activity, which may be at- – Metered Dose Transdermal System vascular and gallbladder disease. The tributed to the absence of the 19-me- (MDTS): Similarly, the Metered antagonistic effect of E on breast tis- thyl radical and the addition of the 16- Dose Transdermal System (MDTS),

sue in the presence of E2 may be ben- methylene substitute, which pro- which is in the initial stages of devel- eficial for the breast. motes binding to and transactivation opment, is a fast-drying liquid formu- of the PR [397, 627]. lation used in a non-occlusive spray 4.3. New Progestins used for – It does not bind to the androgen containing NES dosed via a precisely Hormonal Contraception receptor and is therefore not andro- engineered system delivering the Trimegestone [602] genic. drug to the skin surface [189]. NES is Pharmacological profile [600, 718], – It does not bind to SHBG. combined with a safe skin penetration – Trimegestone (TMG) is a 19-norpro- – NES binds to the glucocorticoid enhancer – octisalate, which forms a gesterone derivative with strong pro- receptor but does not exert glucocor- reservoir within the skin wherein the gestational activity. ticoid activity in in vivo assays at the drug is slowly absorbed into the cir- – TMG is a weak and has doses required for its contraceptive culation over a duration of several modest antimineralocorticoid activ- efficacy [397]. hours. A pharmacokinetic trial of this ity. – As NES has the highest antiovulatory new transdermal delivery system has – In preclinical studies, it was demon- action among existing progestins, a demonstrated the feasibility of achie- strated that TMG has a limited effect very low dose could be used and deliv- ving serum levels of NES sufficient to on the GABA-ergic (γ-aminobutyric ered from non-oral delivery systems. block ovulation and hence provide ef-

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fective contraception. A spray formu- is mediated at the hypothalamic and ment, providing additional non- lation incorporating both NES and an pituitary levels. contraceptive benefits for women’s estrogen, either E2 or EE, is undergo- – In animal models some antiandro- health. ing clinical trials. genic effect was demonstrated [161]. – No androgenic, estrogenic or gluco- Contraception: – Implant: NES has been tested in the corticoid activities could be found – NOMAC has been tested for its con- form of a single implant releasing [414]. traceptive action in the form of oral 100 µg of NES per day administered – NOMAC has been shown to be neu- pills and subdermal implants. Clinical to lactating women in a 2-year study tral on the carbohydrate and lipid me- trials with Uniplant, a single silastic [453]. No pregnancies were reported tabolism [414]. capsule containing NOMAC, have in 2195 woman-months of exposure, shown its efficacy in preventing preg- and implant users demonstrated sig- Rationale: nancy [37, 121]. nificantly less irregular bleeding – The majority of older progestogens, Its mechanism of action has been at- compared to copper-T IUD users. i.e. 19-nortestosterone derivatives, tributed to a high antigonadotropic This progestin also has the advantage were synthesized primarily for their activity leading to blockade of ovula- of being safe for infants as NES is not antigonadotropic activity as a compo- tion and prevention of follicular active orally and is quickly destroyed nent of hormonal contraception in growth, as well as changes in the cer- in the gastrointestinal tract. Massai et combination with an estrogen. vical mucus, endometrial vasculari- al. (2001) [453] followed the growth NOMAC, a 19-norprogesterone de- zation and endometrial architecture of infants who were breastfed by rivative was designed to show highly [37, 39]. mothers receiving an implant of NES selective binding to the progesterone – At an oral dose of 1.25 mg/day, and found no difference in infant receptor; furthermore, it is relatively NOMAC has been shown to suppress growth and development as compared lacking in competitive affinity to ovulation, while at higher doses of 2.5 with those who were breastfed by other steroid receptors. or 5 mg/day, full suppression of both mothers using the IUD. – NOMAC exerts strong antiestrogenic ovulation and follicular development effects at the level of the endometrium is seen [43]. Summary: and has potent antigonadotropic ac- – A new OC has been developed re- Nesterone is not orally active and can- tivity without any residual androgenic cently combining NOMAC and E2 not be used for oral hormonal contracep- or glucocorticoid properties. showing a high contraceptive efficacy tives. It can be used for vaginal rings, and good bleeding control 84]. In the vaginal gel, transdermal “spray-on” con- Clinical indications: near future a new regimen with natural traceptives etc. – NOMAC has been used successfully estrogens (estradiol) in combination for the treatment of some gyneco- with (NOMAC) Nomegestrol acetate logical disorders, such as menstrual (Organon, Schering-Plough now The following chapter about NOMAC is irregularities, dysmenorrheal and MSD) will be available as an oral con- mainly based on a review on Nome- premenstrual syndrome. It has been traceptive [473]. NOMAC has been gestrol acetate and its pharmacology, approved in Europe as a mono- tested clinically in phase III trials as safety profile and therapeutic efficacy therapy for the treatment of the an oral contraceptive with 1.5 mg by Lello (2010) [415] and Mueck & menopausal syndrome, menorrha- estradiol and 2.5 mg NOMAC (MSD) Sitruk-Ware (2011) [473]. gia, and in combination with an and is about to be approved by the estrogen for the treatment of meno- FDA and the European authorities. Pharmacological profile: pausal symptoms. – Nomegestrol acetate is a 19-norpro- – In-vitro data suggest that NOMAC Combined oral contraceptive with gesterone derivative, which is also preserves the beneficial hemostatic NOMAC and estradiol: characterized by the absence of a me- effects of estrogen; furthermore Different formulations of NOMAC as an thyl group at the 19 position [79]. NOMAC has a neutral or beneficial agent in oral contraceptives have been – Absorption of NOMAC is rapid after effect on lipid profiles, and does not studied: as a single agent, in combina- oral administration, reaching a peak adversely affect glucose metabolism tion with ethinylestradiol and with natu- serum concentration within 4 hours, or bodyweight. ral estradiol. Modern formulations of the with a terminal half-life of approxi- – NOMAC has shown a lack of prolif- oral contraceptives combine different mately 50 hours. This long half-life erative activity in normal and cancer- progestogens and natural estrogens with especially results in the high contra- ous breast tissue, and does not have a variations of the cyclic intake. Previous ceptive safety of NOMAC in case of deleterious effect on bone remode- attempts to replace ethinylestradiol with pill-taking errors and provides a sta- ling. natural estradiol resulted in an inad- ble bleeding pattern. – The potent antigonadotropic proper- equate bleeding pattern. – NOMAC is a potent antigonadotropic ties and other beneficial metabolic Due to the low estrogenic effect in com- agent in women and exerts a high pro- and pharmacological characteristics bination with the long half-life, NOMAC gestational action although it is lower suggest that NOMAC can also be an has been proven to provide good cycle than that of Nesterone and Trime- effective progestin for use in combi- control in earlier studies. gestone. As with other progestins, the nation with an estrogen in oral estro- The monophasic oral contraceptive con- antigonadotropic action of NOMAC gen/progestin contraceptive treat- taining NOMAC 2.5 mg and 17-beta-

112 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills estradiol is administered in a 24/4-day VTE and pulmonary embolism in  5. Special Combinations cycle [473]. oral combined contraception with of Combined Hormonal Contraceptive efficacy: NOMAC is doubled. The pro-throm- Contraceptives At a dosage of 1.25 mg, NOMAC has botic effect of progestogen deriva- proven antigonadotropic activity and ef- tives in oral contraceptives may be 5.1. Progesterone Receptor fectively inhibits ovulation, although due to nitric oxide effects, which Modulators follicle growth is possible. might be induced by glucocorticoid – Definition: Progesterone receptor Cyclic dosages of 2.5 to 5 mg/day lead to activity. As NOMAC is a highly spe- modulators (PRMs) are defined as suppressed ovulation and follicle devel- cific progesterone stimulator with any molecule that binds the - opment [43, 122]. The pharmacological low additional properties, it can be binding domain of the progesterone properties of orally administered assumed that the relatively low VTE- receptor (PR), leading to the tissue- NOMAC were studied in 10 clinical risk is based on this feature of specific activation and/or inhibition trails [415]. A subdermal implant with NOMAC. In premenopausal women, of the downstream hormonal re- 55 mg NOMAC also showed the effec- NOMAC did not change the glucose sponse. tive suppression of ovulation [121]. tolerance, fasting blood glucose and – Substances and PRM profile: In the NOMAC also interacts with the cervical insulin levels. past a variety of PRMs with antago- mucus, with a proven loss of spinn- – Data on cancer development in post- nistic (i.e. full antagonist: mifepri- ability, ferning pattern and high density menopausal women with NOMAC as stone), partial agonistic as well as an- of the midcycle mucus having additional HRT suggest an antiproliferative ef- tagonistic (i.e. ) and contraceptive potential [95]. fect in breast tissue [93]. agonistic profile (i.e. comparator: Bleeding control: Nomegestrol acetate – Studies also suggest a beneficial ef- progesterone) have been developed. was studied as a single agent (cyclical fect on bone remodelling. – Indications: PRMs have been used in oral intake of 5 mg) in the treatment of – Overall, NOMAC is well-tolerated. contraceptive research as well as the progesterone deficiency, i.e. menstrual Nausea, headache, breast tenderness treatment of fibroids, endometriosis irregularities, premenstrual syndrome, or irregular bleeding were the most and heavy or irregular menstrual mastodynia, functional uterine bleed- commonly reported adverse events. bleeding [455]. Those with progester- ings, dysmenorrhoea and menorrhagia – A randomized comparative multi- one antagonist activity have potential of fibromas. Menstrual bleeding distur- centre trial to assess the contraceptive application in contraception and the bances resolved or improved in 81.3% of efficacy and general safety was con- treatment of uterine leiomyomata and subjects [105]. ducted in over 4000 women [576, endometriosis. Recently, new clinical 577]. applications of , asopris- Studies with NOMAC/E2 showed a nil (J867), CDB-2914 and good cycle control [84, 588]. Summary: have come under development [475]. Metabolic side effects: The oral appli- – NOMAC shows promising properties Some PRMs (i.e. ) exert cation of NOMAC as a single agent and as a contraceptive progestin. anti-estrogenic effects, either through in combination with estradiol and – The highly specific binding to pro- partial progesterone receptor agonist ethinylestradiol has a favourable toler- gestogen receptors and the lacking or activity [583, 712] or they exert these ability profile and neutral metabolic minimal effect of binding to other effects independently of the proges- characteristics. This profile is achieved steroid receptors contributes to the terone receptor itself, i.e. by up-regu- through the almost exclusive binding to good tolerability and metabolic pro- lation of the re- the progestogen receptor with little in- file. sponse [605, 477]. These PRM lead teraction with other steroid receptors – Furthermore, the favourable effects to a dose-dependent suppression of [397, 473]. The effect on lipid und glu- on estrogen metabolism, human estrogen-induced mitotic activity and cose profiles, thromboembolic risk and breast tissue and cancerous breast tis- to glandular secretory changes [712]. other markers of cardiovascular activity sue are additional advantages. PRMs are also efficient in improving is low. – New contraceptives with natural bleeding problems associated with con- estradiol have the potential for a traceptive hormonal implants [92, 701]. The potential risk of clinically signifi- higher safety than EE-based OCs due cant interactions between NOMAC and to the lower impact of estradiol on the – Contraceptive trials [501]: modifiers of CYP3A4 such as rifampicin synthesis of estrogen-dependent liver ● Different trials examining the co- or must be taken into ac- proteins. administration of antiprogestinic count. – However, large safety surveillance compounds (also called selective studies are still required once the new progesterone receptor modulators) Adverse events: E2-based combinations become with progestin-only pills have been – Metabolic side effects: The effect available and it is to be hoped that conducted to control this adverse on plasminogen and fibrinogen lev- preferential prescription and biased effect of progestins on the endo- els as well as the overall risk of ve- results will be avoided. metrium [681]. nous thrombosis has been shown to ● Croxatto et al. demonstrated that be low [42], although there was a a sequential administration of slight, significant increase in anti- mifepristone and nomegestrol ac- thrombin levels. The relative risk of etate could improve irregular bleed-

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ings [133]. In this study, adminis- that binds the ligand-binding domain The neural tube closes by the 28th day of tration of mifepristone (5 mg/day) of the progesterone receptor (PR), gestation. If this process is disturbed in during the first part of the men- leading to the tissue-specific activa- the upper part of the spine, this may lead strual cycle inhibited ovulation tion and/or inhibition of the down- to anencephaly, while closure defects of without decreasing estradiol secre- stream hormonal response. the lower part result in spina bifida. On a tion and allowed endometrial – Various PRMs with antagonistic (i.e. global level, about 300,000 children are growth. In the second part of the full antagonist: mifepristone), partial born each year with neural tube defects. menstrual cycle, nomegestrol agonistic as well as antagonistic (i.e. According to a national study, the preva- acetate inhibited ovulation and ulipristal acetate) and agonistic pro- lence in Germany was about 5.7 per regular menstruation was observed file (i.e. comparator: progesterone) 10,000 births [431]. at the end of the 28 days’ treatment. have been developed. ● Finally SPRMs administered alone – Mono-preparations have been analy- The prevalence is particularly high in ar- in a continuous manner are cur- zed as to whether they can suppress or eas of the world where the folate levels rently evaluated as estrogen free postpone ovulation, act as modulators are traditionally low, e.g. in the Northern contraception. Daily low doses of of the endometrial surface preventing part of the People‘s Republic of China mifepristone (2 mg/day) inhibit implantation without disturbing the [421]. ovulation, prevent secretory trans- normal menstrual cycle or be used as formation of the endometrium and an abortifacient. Folate and folic acid induce amenorrhea [63, 411, 623]. – Mono-preparations (i.e. 30 mg ulipri- Folic acid is a purely synthetic form of ● Pei et al. (2007) [507] have re- stal acetate) are used for emergency vitamin B9, which is effective only after cently demonstrated that weekly contraception. appropriate biotransformation in the administration of mifepistone (25 – In combination with combined estro- body. The naturally occurring form in and 50 mg) also inhibited ovu- gen/progestin contraceptives, they food are folates, with L-5-methyl-tetra- lation. This weekly intake may might improve the bleeding pattern hydrofolate (L-5-MTHF) being the pre- contribute to improving compli- by counteracting the progestin activ- dominant form in humans (approx. ance. ity at the time the withdrawal bleed- 98%). Folates are essential for a healthy ● The use of SPRMs alone has the ing should occur. embryonic development. very important advantage of pro- – Weekly administration, sequential viding ovulation inhibition with- discontinuation or administration of Neural tube defects and folate out lowering estradiol levels [628] progestins may be other options. Fi- Andrew E. Czeizel and his group pub- and may not result in estradiol dep- nally, vaginal routes of administration lished the first randomized study show- rivation symptoms or long term of SPRMs and progestins are cur- ing a dramatic reduction in the expected estrogen deprivation consequen- rently under evaluation [603]. Fur- incidence of neural tube defects after ces. thermore, intrauterine application is a substitution with multivitamins includ- ● However, as the effect of estradiol promising approach. ing folic acid. Furthermore, some other is unopposed, the impact on the en- – Oral formulations of potent PRMs malformations such as heart defects, uri- dometrium through long term use with an antagonistic profile have a nary tract anomalies, and stomach steno- of SPRMs is unclear. It may result high potential for illegal abuse as sis were reduced [142, 143]. in simple hyperplasia as previously abortifacients. Furthermore, sub- A large Chinese study also showed these described in women treated for stance-specific adverse events must results [51]. fibromyomas [628]. be considered. The Centers for Disease Control and Pre- ● The aspects observed may also vention (CDC) and the U.S. Preventive correspond to class specific modi- 5.2. Special COC Compositions Services Task Force (USPSTF) recom- fications of the endometrium [85, 5.2.1. Oral Contraceptives with Folate mend that all women of childbearing age 263, 406, 712]. Supplementation supplement their diet with at least 400 ● Intrauterine administration of Neural tube defects mcg of folic acid daily to reduce the risk antiprogestins has also been evalu- Even in countries with high average in- of a neural tube defect (NTD) [80, 667]. ated showing promising bleeding comes where pregnancies and deliveries Despite multiple studies and well-de- patterns and histological profiles are believed to be as safe as possible, signed information campaigns for the [239]. This may overcome the there is a perinatal mortality of 5–7 per periconceptional use of folic acid, the previously described potentially 1000 births, with 20% resulting from decline in neural tube defects in coun- negative endometrial effect. congenital malformation [610]. tries with and without folic acid food Substance-specific adverse events supplementation has not met expecta- led to the discontinuation of the Of all congenital anomalies, structural tions. The likely reason is that the cam- development of clinical phase III malformations such as heart defects or paigns are failing to reach out especially trials with asoprisnil due to endo- neural tube defects play the dominant to those women who have an increased metrial changes in patients [269]. role. Especially since the risk of birth defects, a low standard of catastrophe, it has been known that there education as well asyounger age and Summary: are sensitive periods in embryonic de- who experience unplanned pregnancy – Progesterone receptor modulators velopment in which specific abnormali- [167]. Another reason is selective adher- (SPRMs) are defined as any molecule ties can occur or may be prevented. ence to the intake of medicines and nu-

114 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills tritional supplementation. The women’s is too late to substitute folate or folic acid The financial and social burden due to compliance with the folic acid supple- after the beginning of a pregnancy, espe- neural tube defects has been calculated mentation is still not sufficient [76]. cially since it takes 6–8 weeks until suf- in various preventive strategies, e.g. ficiently high folate levels have been food fortification in the US [47]. The Women who plan to become pregnant, achieved [597]. health economic benefits of integrating should take a daily dose of 400 µg of oral contraception with folate supple- folic acid starting not later than four Folate deficiency in oral contraceptive mentation has been shown by a model weeks before the onset of pregnancy. users calculation. About 50% of neural tube The folate treatment should be main- In the first month after discontinuing an defects in Germany could be prevented tained during the first trimester of preg- oral contraceptive, more than 20% of by this approach [499]. nancy. Folic acid is a synthetic formula women and after three months about The risk of neural tube defects can be that is activated after biotransformation 50% were pregnant [131]. After 12 significantly reduced if women increase in the body [516]. Compared to other months, 70–90% of the former oral con- their folate levels. The combination of B-vitamins, the daily supply of folate in traceptive users become pregnant [40]. oral contraceptives with folate is an in- food in Germany is by far the lowest. A survey in France showed that about novative and useful concept that can rep- The daily intake of folate by adults in one third of pregnancies are unplanned/ resent a significant advance in women’s Germany is about 80–90% below the unintended, and about two thirds of health. reference values recommended by the them occur while contraceptive methods German Society for Nutrition [460, including oral contraception are used New oral contraceptives with folate 645]. On average, the daily dietary up- [469]. Especially long-term use of a supplementation have received FDA take is only 250 µg whereas it should be medication like the oral contraceptive is approval 400 µg. Because of the importance of associated with intake errors [498]. Dis- A new class of oral contraceptives con- folate for cell division processes, the continuation of the oral contraception is taining folate (L-5-MTHF) has been de- demand during pregnancy rises to 600 often not reported to or discussed with veloped, reducing the risk of neural tube µg/day, whichmeans an increase of 50% the women’s gynecologist. The chance defects in unintended, unplanned preg- [460]. to receive preconceptional medical ad- nancies or pregnancies occuring directly It is not possible to ensure an adequate vice is missed in most cases. after the cessation of the oral contracep- folate supply based on daily nutrition In women using an oral contraceptive tive. alone. This would require a daily vegeta- containing folate, up to 12 weeks after The first oral contraceptive containing ble and fruit consumption of 600–700 g. withdrawal of the pill, folate levels re- levomefolate (L-5-MTHF), a In fact, however, on average, the daily main at a sufficient level for protection folic acid metabolite, was Beyaz™, uptake is 260 g. In more than 50 coun- against neural tube defects and other which was approved by the FDA on Sep- tries around the world, food is voluntar- early embryonic defects [34]. tember 24, 2010 [302]. It is manufac- ily or mandatorily supplemented with The addition of folate to an oral contra- tured by Bayer HealthCare Pharmaceuti- folic acid – with remarkable success: the ceptive is an innovative, targeted ap- cals Inc. and is based on the previously number of embryonic development de- proach to ensure a protective folate level approved oral contraceptive YAZ™. fects caused by folate deficiency, espe- in women of reproductive age before While thedoses of estrogen and proges- cially neural tube defects, has decreased conception. tin (ethinyl estradiol 20 µg; drospirenone significantly [50, 59]. 3 mg) are the same, Beyaz™ also con- However, to date, there is no mandatory Rationale for folate supplementation tains 0.451 mg of levomefolate calcium. folic acid supplementation of food in in oral contraceptives Beyaz™ shares the previously approved any European country. Health authori- The concept of a folate-supplemented indications of YAZ™: pregnancy pre- ties rely on the voluntary principle, OC makes sense in many ways. vention, treatment of premenstrual dys- which does not lead to the desired result. – Users of oral contraceptives benefit phoric disorder (PMDD) symptoms in Many European countries justify this by most from adequate folate levels com- women who use OCs for contraception, legal regulations; in Germany, Article 2 pared to all other population groups. and treatment of moderate acne in pa- of the Basic Law (“right to free develop- – Women who use oral contraceptives tients aged 14 years and older who have ment of one’s personality”) precludes receive regular gynecological care. chosen to use an OC for birth control. such action. The discussion about food Gynecologists have the opportunity Beyaz® has been approved for the sec- fortification and potential risks of to raise the awareness for the useful- ondary indication of raising folate levels mandatorily fortified food is ongoing ness of folate supplementation. to reduce the risk of neural tube defects [117, 499]. – A woman who uses oral contracep- in women who conceive while using the tives is not interested in questions of product or shortly after discontinuation. Folate supplementation should start folate supplementation as a prepara- Users should be counseled prior to tak- before pregnancy (preconceptionally) tion for pregnancy as she is actively ing the drug to report whether they are The neural tube closes at the end of the trying to prevent a pregnancy. In fact, taking folate supplements. Folate sup- first month of pregnancy (24 to 28 days unintended, unplanned pregnancies plementation should be maintained after after conception), at a time when many occur also during the intake of oral discontinuing the oral contraceptive women still have not realized that they contraceptives, mostly due to inad- Beyaz™ [287]. are pregnant. Even before conception, equate intake of one or more pills in a The other oral contraceptive used to an adequate folate status is necessary. It cycle. raise the folate level in women is

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Safyral™, which received FDA approval skin rashes and depression. The symp- netic testing for lactase gene polymorph- on December 16th, 2010 [303] (Bayer toms may increase with age. isms may confirm the diagnosis of a pri- HealthCare). It is an oral contraceptive Lactose intolerance can have different mary lactase deficiency; homozygous raising folate levels in women who causes. The primary type of lactose in- carriers of the polymorphism developing choose an oral contraceptive for birth tolerance is caused by a genetic defi- a manifest lactose intolerance with a control. Safyral™ is based on a 21/7 day ciency of the enzyme lactase. Secondary likelihood of 95% are as follows: regimen containing drospirenone 3 mg, lactase deficiency occurs due to damage – 13 910 TT (in 40% of all cases): no ethinyl estradiol 30 µg and levomefolate or atrophy of the epithelial layer of the evidence of Primary Lactose Intoler- calcium 451 µg. small intestine. Diseases leading to ance secondary lactase intolerance are acute – 13 910 TC (in 45% of all cases): no The FDA approval was based on data gastroenteritis, persistent diarrhea, small evidence of Primary Lactose Intoler- from two clinical trials [306]. The first bowel overgrowth or ance, carrier was a U.S. multicenter, randomized, [252]. – 13 910 CC (in 15% of all cases): double-blind, parallel-group study, a 24- About 70% of the world’s population predisposition to Primary Lactose In- week clinical trial involving 379 healthy suffer from lactose intolerance in vari- tolerance [326]. women aged 18–40 years. Data showed ous degrees [252]. There are different that YAZ™ (drospirenone 3 mg, ethinyl regional prevalences of lactose intoler- Clinical options in patients with estradiol 20 µg, Bayer HealthCare) in ance worldwide. In Asia and Africa the lactase deficiency and contraception combination with 451 µg of levomefol- prevalence is extremely high, whereas in After diagnosis, the treatment of lactose ate calcium (Metafolin) increases folate Western Europe, the US and Australia, intolerance consists of avoiding food levels significantly from baseline com- the syndrome is not so dominant, but still containing lactose [410] or in special pared to YAZ™ alone: RBC folate (420 common. It is estimated that 15–20% of cases of enzyme replacement. ± 347 nmol/L vs. 34.3 ± 171 nmol/L, adults in Germany suffer from this con- Pharmaceuticals contain a small but pos- respectively) and plasma folate (15.8 ± dition [642]. Genetic testing for poly- sibly relevant amount of lactose. Users 20.4 nmol/L vs. –2.2 ± 14.6 nmol/L, re- morphism can be used to diagnose the should be informed that lactose as an ex- spectively). primary type of lactose intolerance. cipient in tablets may worsen their A separate European study based on gastrointestinal symptoms [514]. Wo- Yasmin® (drospirenone 3 mg, ethinyl A common diagnostic test is the lactu- men with severe symptoms after a lac- estradiol 30 µg, Bayer HealthCare) in lose hydrogenbreath test. Additional ge- tose challenge should be informed about combination with either 451 µg of Metafolin or 400 µg of folic acid for 24 weeks followed by 20 weeks of treat- Table 4. Lactose content of various oral contraceptives. ® ment with Yasmin only found that the Oral contraceptive Hormone Excipients Brand Brand Metafolin treatment produced the maxi- name name mum mean increase in plasma folate (Germany) (US) (33.5 ± 14.5 nmol/L) and in RBC folate progestin-only pills levonorgestrel lactose Microlut® (782 ± 260 nmol/L) levels at 24 weeks. monohydrate 33,1 mg However, folate-containing oral contra- progestin-only pills desogestrel lactose 1-water Cerazette® ceptives have not yet become available 8 mg on the European market. combined oral contraceptive EE lactose 52,15 mg YAZ® (20 µg EE) + drospirenone 5.2.2. Lactose-Free Oral Contraceptives combined oral contraceptive EE Lactose intolerance (30 µg EE) + drospirenone lactose 46 mg Yasmin® Zarah™ The term “lactose intolerance” refers to combined oral contraceptive EE lactose- Belara® the partial or total inability to digest lac- (30 µg EE) + chlormadinone monodydrate tose. The lactose is a carbohydrate found acetate 69,5 mg in milk and other dairy products and combined oral contraceptive EE lactose Valette® may be concealed in products with spe- (30 g EE) + dienogest 1-water 27 mg (change of cial ingredients, as well as in most phar- ingredients) maceuticals. Lactose is cleaved in the combined oral estradiol-valerate small intestine by the enzymatic activity contraceptive with + dienogest lactose 50 mg Qlaira® Natazia™ of lactase. A lack of lactase or its insuffi- estradiol cient activity results in malabsorption of Lactose-free oral contraceptives: the disaccharide. Malabsorption leads to Germany US a clinical syndrome with at least one di- progestin-only pill ethynodiol diacetate Femulen® Femulen™ gestive symptom: diarrhea, abdominal combined oral contraceptive 30 µg EE and Nordette™/ Portio™ pain, nausea, flatulence and/or bloating. levonorgestrel The severity of the symptoms depends combined oral contraceptive chlormadinone acetate Enriqua® on the total enzyme activity and on the and 30 µg EE combined oral contraceptive 30 µg EE, dienogest Valette®, lactose intake. In severe cases, lactose Maxim® intolerance can result in malnutrition,

116 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Oral Contraceptive Pills the fact that lactose-free oral contracep- Iron deficiency is a fat-soluble vitamin that tives are available. Alternative contra- – Iron deficiency is one of the most plays an important role in bone metabo- ceptive methods without lactose are commonly known forms of nutri- lism and seems to have some anti-in- shown in Table 4: tional deficiency. flammatory and immune-modulating – Injections, implants of progestogen – In the human body, iron is present in properties. In addition, recent epidemio- – Contraceptive patches all cells and has several vital func- logic studies have examined the link be- – Intrauterine devices (IUD) tions – as a carrier of oxygen to the tween low vitamin D levels and multiple – Intrauterine systems (IUS) tissues from the lungs in the form of disease states. Low vitamin D levels are – Barrier methods (diaphragms, con- hemoglobin, as a transport medium associated with increased overall and doms and cervical caps). for electrons within the cells in the cardiovascular mortality, cancer inci- form of cytochromes, and as an inte- dence and mortality, and autoimmune Contraception in patients with lactase gral part of enzyme reactions in vari- diseases such as multiple sclerosis [142, deficiency ous tissues [273]. 396]. Symptoms of a lactose intolerance fre- – The direct consequence of iron defi- quently occur after taking 3–5 g lactose. ciency is iron deficiency anemia. Iron The majority of the general population It can be seen that the majority of those deficiency is quite common. In 1998, has insufficient 25-hydroxyvitamin D affected will tolerate up to 12 g of lac- it was found in in 9–11% of women (25[OH]D) levels. This is mainly a con- tose per day without symptoms under a between 12 and 19 years, while iron sequence of lifestyle related reductions low-lactose diet [429]. This corresponds deficiency anemia was present in in sunlight exposure and subsequently to 240 ml of cow’s milk. In most cases 2–3% of all subjects in the US [81]. reduced vitamin D synthesis in the skin. the intake of one tablet daily containing less than 50 mg of lactose should have Medications such as oral contraceptives Vitamin D receptors (VDR) have been little consequence 514]. can lighten heavy menstrual flow [312] and discovered in almost all human cells and prevent loss of iron during menstruation. recent studies suggest an important role Summary: of the vitamin D endocrine system for Lactose intolerance is common, but According to Frassinelli-Gunderson et several extraskeletal diseases (e.g. ad- shows high local and ethnic variability. al. (1985) numerous cross-sectional and verse pregnancy outcomes, reduced fer- In Germany, the incidence is relatively some short-term longitudinal studies in- tility and polycystic ovary syndrome low, but no fewer than 15% of the dicate that OCs consistently elevate se- (PCOS), as well as cancer). women are affected by abdominal symp- rum iron,the total iron-binding capacity toms following lactose intake. Based on and serum transferrin while hemoglobin OC use increases circulating levels of clinical symptoms and in some cases the and hematocrit remain essentially un- 25-hydroxyvitamin D, and should be results of gene tests, the elimination of changed [75, 347, 374, 449, 488, 489, considered when interpreting values ob- lactose from the daily diet is recom- 522, 523, 736]. tained for clinical evaluation or nutrition mended. In severe cases, the use of research [233]. lactase tablets to support digestion may In the US, the norethindrone-containing be necessary. Compared to the dietary OCs Loestrin and Loestrin 24 Fe have New patents cover the use of vitamin D intake of lactose, the lactose content per iron supplements in the placebo pills. in combination with traditional oral hor- tablet is relatively low (50–70 mg/tablet monal contraceptives and genestin versus 12 g containing in 240 ml of Summary: [309]. milk). In most cases symptoms start – Iron supplementation is only avail- when 3–5 g lactose are ingested. In- able in some brands of OC in the pla- Summary: dividual responses have been observed. cebo pills. – Vitamin D is a very promising vita- – Oral contraceptives elevate serum min with various benefical extra- A person with lactase deficiency symp- iron, the total iron-binding capacity skleletal actions on e.g. adverse preg- toms or lactase deficiency proven by and serum transferrin, while hemo- nancy outcomes, reduced fertility and gene tests can avoid lactose in oral globin and hematocrit levels remain polycystic ovary syndrome (PCOS), contraceptives using specific brands essentially unchanged as well as cancer or choosing other contraceptive meth- – Oral contraceptives lighten heavy – Improvement of vitamin D status ods. menstrual flow [312] and prevent loss should be a goal for the general of iron during menstruation. healthcare system as well as for gyne- 5.2.3. Oral Contraceptives With Iron – Iron supplementation is useful in spe- cologists. Supplementation cial cases due to the of iron in – No preclinical studies registered at For women aged between 14 and 18, the individuals with iron store disease in www.clinicaltrials.gov (FDA Home- recommended daily intake of iron is 15 the liver. page for clinical trials) mg and for 19–50 years 18 mg [341]. In humans, iron is an essential component 5.2.4. Vitamin D-Supplemented Oral 5.2.5. Genestin Supplemented Oral of proteins involved in oxygen transport Contraceptives Contraceptives [144, 341]. It is also essential for the Vitamin D is classically known to pro- are a diverse group of regulation of cell growth and differentia- tect against rickets and is a standard plant-derived compounds that structur- tion [19, 58]. treatment for osteoporosis patients. ally or functionally mimic mammalian

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 117 Oral Contraceptive Pills estrogens and show potential benefits for total T and by 20 to 2 pmol/l for free T The addition of DHEA to COCs did not human health. Potential beneficial ef- after 3 treatment cycles of COC. This cause any side effects and DHEA had no fects of phytoestrogens on breast and study was reported at the COGI Con- effect on the incidence of hirsutism in prostate cancers, cardiovascular disease, gress in Berlin in November 2010. the studies in Amsterdam and Liège last- menopausal symptoms and osteoporosis ing 10 and 12 months respectively. The have been examined in various trials Since the natural human androgen de- incidence of acne was comparable to the [496]. Isoflavones as i.e. genestin are hydroepiandrosterone (DHEA) is partly incidence without pill use. tested in clinical trials mainly for female metabolized into T after oral administra- postmenopausal hormonal replacement tion, restoration of T levels during COC According to the Bayer Annual Report (e.g. vasomotor menopausal symptoms) use can be achieved by the concomitant (2008) [285], Bayer HealthCare has per- [416]. administration of DHEA. The studies by formed efficacy and safety studies Pantarhei have shown that with a dose of (phase II) [267] of oral dehydroepi- New patents are covering the use of 50 mg DHEA per day T levels can be (100 mg) as a concomitant genestin (20 mg at least; dose range 50– normalized without exceeding the maxi- therapy to oral contraceptives in women 80 mg) and vitamin D (at least 400 IU) in mum T levels found in regularly cycling complaining of reduced . The pur- combination with traditional oral hor- women not using COCs. pose of the study was to evaluate the ef- monal contraceptives [550]. fectiveness of the study drug on the li- In addition to the normalization of T bido () of women who are Various so-called bioidentical hormones levels, adding DHEA to the contracep- taking oral contraceptives and have ex- some derived from plant extracts have tive pill results in significant clinical perienced libido reductions as a side ef- been chemically modified to be structur- improvements of mood and sexual fect of OCs. The results of these studies ally indishinguishable from human en- function in unselected COC users. The are not yet known. dogenous hormones. first results of a clinical phase II study using the “triple hormone” oral contra- The ARC “triple hormone” concept com- The use of bioidentical hormones in ceptive ARC concept and focusing on bining an estrogen (E), a progestin (P) postmenopausal women is summarized sexual function and safety were re- and an androgen (A) in a COC has been in a review by Cirigliano (2007) [97]. ported in May 2010 at the 11th Congress patented by Pantarhei Bioscience for oral of the European Society of Contracep- contraception. In addition, Pantarhei has Summary: tion in The Hague, The Netherlands. obtained a sub-license on a broad patent – The clinical benefit for a combination The study including 82 women com- owned by BioSante, USA, protecting the of genestin and traditional combined prised a crossover design of two treat- combined use of E, P and A in general. oral contraceptives is not yet evident. ment periods of five months each and Long-term risks of the use of bio- compared use of an oral contraceptive Summary: identical hormones from plant ex- alone to the same oral contraceptive – DHEA is a weak androgen produced tracts have not been evaluated. with the addition of 50 mg DHEA per by the adrenals which acts a precursor day. The study was performed by R. van for androgen synthesis. – Preclinical studies are not registered Lunsen and E. Laan from the Depart- – DHEA-dosage is very high compared at www.clinicaltrials.gov (FDA ment of Sexology of the Academic to the dosage used “off-label” and in Homepage for clinical trials). Medical Center in Amsterdam, The most countries as an OTC drug for Netherlands in close collaboration with substitution in the postmenopause 5.2.6. DHEA-Supplemented Oral the H.C. Bennink and Y. Zimmerman (10–25 mg/day). Contraceptives from Pantarhei Bioscience. In these pill – A preclinical study by Bayer Health- Androgen Restored Contraception users without specific sexual com- Care [267] has been completed, but (ARC) is a novel concept for oral contra- plaints, arousability, genital sensation the dosage of DHEA (100 mg/day) ception, invented at Pantarhei Bioscience, and lubrication improved significantly used in this trial was too high and the a Dutch pharmaceutical company. The in a double-blind study setting. Further- side effects of DHEA in such high concept is based on the fact that the use more a double increase of the frequency dosage in women of reproductive age of combined oral contraceptives (COC’s) of sexual activity and a significant re- are unclear. causes a decrease of androgen levels, duction of the frequency of rejection of – Women with a spontaneous menstrual especially testosterone (T), due to the in- initiation of sexual activity by the part- cycle have significant circulating lev- hibition of ovarian androgen production. ner were observed. els of testosterone, but in women us- According to the literature, T levels de- ing combined COCs testosterone is crease by up to 50%. However, large pro- In the Liège study using validated mood suppressed. spective studies conducted by Pantarhei questionnaires, significant mood im- – Normalization of testosterone levels have shown that the loss of T is more se- provements were observed during 6–12 during the use of COC by adding 50 rious. A phase II endocrinology and months DHEA treatment, all in favor of mg oral DHEA per day improves both safety study performed by J.M. Foidart DHEA use. mood and sexual function signifi- in Liège, Belgium, in collaboration with cantly. As in the case of testosterone Pantarhei Bioscience including 99 pill No effect of DHEA was obtained in two substitution in the postmenopause, use starters has shown a significant me- smaller so-called n = 1 studies in women the effect of testosterone on breast dian decrease by 1.5 to 0.5 nmol/l for with serious mood or sexual problems. cancer might be the crucial issue.

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