Third Generation COC

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Third-generation oral contraceptives are an association of low-dose ethinyl estradiol andpotent testosterone-derived progestins, developed in order to improve general and vasculartolerance. They are highly efficient and well tolerated by most users. Their extensive use hasprovided different key information: oral contraceptives (as well as non-oral ethinyl estradiol-containing contraceptives) can be used in women under the age of 35 years with well-controlled metabolic risk factors and high familial risk of breast cancer. On the other hand,ethinyl-estradiol containing contraceptives are not indicated in women with a high risk ofdeep venous thrombosis, or noncontrolled metabolic and vascular risk factors (includingbeing over the age of 35 years or cigarette smoking), or with a history of breast cancer.Progestin-only contraception is not well tolerated owing to bleeding. Future hormonalcontraception for women with a high vascular risk may contain nontestosterone-derivedprogestins and 17β estradiol, or antiprogestins.

The development of oral contraception was one of the great medical and social revolutions ofthe 20th Century. Oral contraception is still one of the most widely used techniques in manycountries. As defined by the WHO, contraception must be efficient, reversible, affordable andwell tolerated. The potential impact of the use of estrogens and progestins for contraceptionhas been a subject of controversy for the last 10-15 years, especially concerning (arterial andvenous) vascular risk as well as carcinologic risk.

Different generations of oral contraceptives (OCs) have been developed mainly to reducetheir metabolic and vascular risk. This development was based mainly on the knowledge ofintermediate risk markers that, as we now know, are not as reliable as large clinical trials.This text will thus summarize the current knowledge on the development of third-generationOCs, risks and benefits of these compounds and potential future health care specificities inthird-generation OCs users. Current and future tracks of research, in the light of what we havelearnt from third-generation OC use are sure to develop.

Since Carl Djerassi and Gregory Pincus brought the proof of concept of OCs in the early1960s, with a pill containing norethidronel as a progestin and mestranol as an estrogen,many different compounds have been developed. Today 'the pill' is an association of ethinylestradiol (EE) with a synthetic, testosterone-derived progestin, with the exception ofcyproterone acetate (CPA)-containing OCs and the recently developed drospirenone- andchlormadinone actetate-containing OCs. This recent development will be discussed later.The mechanism of action of EE-containing OCs includes inhibition of ovulation via a dualimpact of progestins on the hypothalamus and of EE on the pituitary. In addition, theassociation of a progestin with EE allows good endometrial tolerance.

One of the main drawbacks during the early development of OCs was venous thrombo-embolism, occurring shortly after the beginning of treatment. This risk has been related to theimpact of EE on hepatic synthesis of procoagulant proteins. Other side effects of OCs, suchas hypertension, have also been related to the impact of EE on the hepatic synthesis ofangiotensinogen. OC development then included potent progestins, which allowed reductionof EE doses due to their strong antigonadotropic effect, leading to second-generation OCs.However, all progestins used in OCs until recently were testosterone derivates, their impacton metabolic and vascular risk markers also had to be controlled, and third-generationprogestins were designed to have a reduced potential metabolic and vascular impact.

Third-Generation Oral Contraceptives:Future Implications of Current UseSophie Ouzounian; Lieve Verstraete; Nathalie Chabbert-BuffetExpert Rev of Obstet Gynecol. 2008;3(2):189-201.

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The current classification of OCs into three different generations relies on the progestin used,and its related specific pharmacological profile (Figure 1). Nearly all progestogeniccompounds used in OCs are derived from testosterone or estrogenic derivates. Current first-generation OCs includes norethisterone- and norethindrone acetate-containing pills. Theyare obtained by the addition of an ethinyl radical on carbon 17 while the methyl radical oncarbon 10 and 19 is suppressed. These 18 carbon compounds are also called estranes.They have a high affinity for the progesterone receptor (PR) ( ), a strong anti-gonadotropeactivity, as well as an intermediate affinity for androgen receptors. First-generation OCscontain 35-50 µg EE2/pill in association with a progestin.

Affinity of Progestins for the Different Steroid Hormone Receptors

ProgestinRelative binding affinity for steroid receptors (%)

PR AR ER GR MRProgesterone 50 0 0 10 100Norethisterone 75 15 0 0 0Levonorgestrel 150 45 0 1 75Norgestimate 15 0 0 1 03 ketodesogestrel 150 20 0 14 0Gestodene 90 85 0 27 290Chlormadinone Ac 67 5 0 8 0Cyproterone Ac 90 6 0 6 8Medroxyprogesterone Ac 115 6 0 29 160Nomegestrol 125 6 0 6 0Promegestone 100 0 0 3 53Drospirenone 35 65 0 6 230

The relative binding affinity (%) of the main progestins discussed in this paper for the differentsteroid receptors is indicated. These results are based on in vitro studies and bioassays.Such data are used for a primary prediction of the potential effects of a compound. Asdiscussed in the text this data may be revisited with our current knowledge of the mechanismof action of steroids.AR = Androgen receptor; ER = Estrogen receptor; GR = Glucocorticoid receptor; MR =Mineralocorticoid receptor; PR = Progesterone receptor.



Testosterone-derived progestins and classification.

Second-generation OCs include levonorgestrel-containing pills, of which developmentstarted approximately from 1970 onwards. Levonorgestrel derives from estrone by theaddition of an ethinyl radical on carbon 17 and the suppression of the methyl radical oncarbon 10 and 19, but also has an ethyl radical instead of a methyl at carbon 13. It is amember of the 17 carbon derivates, also known as gonanes. This progestogen has a higheraffinity for PRs and a higher affinity for the androgen receptor than first-generation OCs,based on in vitro studies and bioassays. In association to the progestin, second-generationpills contain 20-50 µg per pill.

Third-generation pills appeared in the 1990s. They include desogestrel-, gestodene- andnorgestimate-containing pills.[1] They are derived from levonorgestrel by suppression of theketone function at carbon 3 (except for gestodene) and addition of a methylene radical atcarbon 11. They have a reasonable affinity for the androgen receptor ( ) and were supposedto have less metabolic side effects.[2] Third-generation pills contain 15-30 µg EE2/tablet.

Contraindications of Oral Contraceptives

• Cardiovascular disease• Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism)• Family arterial or veinous thromboembolic disease (homocysteinemia, Factor VLeiden mutation)• Cigarette smoking and age > 35 years• Migraines with aura• History of ischemic heart disease• History of stroke• History of complicated valvular disease• Major surgery with long immobilization• Noncontrolled arterial hypertension• Diabetes with micro- or macroangiopathy• Breast cancer• Endometrial cancer



• Endometrial cancer• Liver carcinoma or adenoma• Undiagnosed bleeding• Pituitary tumors (microprolactinoma may receive oral contracteptives)• Systemic lupus erythematosus (without signs of evolutivity or markers of deep veinthrombosis risk may receive oral contraceptives)• Porphyrias

As discussed in the text these contraindications have been re-evaluated and reducedduring the 45 years of experience of oral contraceptives, with the improvement of theirtolerance profile. However, reduction in ethinyl estrogen doses and development ofthird-generation progestins did not solve the problem of high vascular risk.

Three associations of EE with a nontestosterone-derived progestin (CPA, chlormadinoneacetate and drospirenone) are currently available and will be discussed in the 'Five-yearview' section. These compounds could be associated with a new 'fourth-generation' class,although the progestins used in these associations are from a different origin, which makesthe class rather heterogeneous.

Most OC formulations are monophasic, containing a fixed dose of estrogen and progestin. Bi-or triphasic pills were also developed to mimic the physiological cycle. Data on the specifictolerance profile of these latter formulations are very scarce and will thus not be discussedindividually.

Third-generation OCs, as well as first- and second-generation ones, are highly effective.Pearl indices range between 0.07 and 2.1 pregnancies per 100 women-years of treatment.[3]They allow excellent cycle control if compliance is good and reduce premenstrual bloating,dysmenorrhea, premenstrual mood fluctuations and breast tenderness.[4]

New progestins associated in third-generation OCs were created to minimize androgenicside effects, such as hirsutism. They also induce less nausea and lipid profile modifications.[5]

The different progestins used in OCs were compared in a review from the CochraneDatabase including 22 trials.[6] Gestodene-containing OCs are associated with less inter-menstrual bleeding, but similar spotting, breakthrough bleeding and absence of withdrawalbleeding. In a recent study comparing the tolerance of different contraceptives in 2863 usersno differences in general and gynecological tolerance profile were found between third-generation OCs and other EE-containing OCs.[7]

Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism(PE), is the most common serious adverse event among women using OCs. The riskdepends on the type of OC, but is also strongly influenced by other risk factors such asincreased body weight, recent surgery, history of DVT and thrombophilia. In this last case,DVT occurring at the beginning of the use of OCs appears to be a frequent diagnosis. In fact,first year prescription is associated with a higher risk of this unwanted event.

The initial case reports regarding DVT and PE in women using OCs were published shortlyafter their first prescription.[8] The main cause of these problems was the strong dose ofestrogens. The development of OCs with lower estrogen doses dramatically reduced the risk.However, when third-generation pills were developed, different initial studies suggested thatthose preparations increased DVT risk. In 1995, publications of the WHO cardiovasculardisease group of experts,[9] followed by various other studies,[10-12] suggested that third-generation pills induced a two- to fourfold relative risk of DVT compared with levonorgestrel-containing OCs. On the other hand, three other studies were unable to find any increase inthe risk for DVT in third-generation pill users.[13] The DVT risk returned to baseline after



discontinuation of OCs. The impact of the initial reports on the risk of DVT in third-generationpill users has been very important. In fact, a 'pill scare' occurred in some countries resulting innumerous unwanted pregnancies.[14] Initial discussions suggested that studies might havebeen biased. After extensive debate in the literature, a consensus has been reached thatthose biases can not completely explain the increased risk.[9,15,16] However, even if anincreased risk is observed, the absolute risk remains very low. With a baseline risk evaluatedto one in 10,000 person-years, third-generation pill-related risk would rise to 2-4/10,000person-year, which is quite low.[13]

This increased risk of DVT observed with third-generation OCs, containing lower doses ofestradiol and progestins designed to have a minor impact on metabolic and vascular riskfactors, was rather unexpected and has been investigated. Middeldorp et al. have reviewedpublished data on the impact of progestins on DVT risk.[17] OCs increase prothrombin,Factors VII, VIII and X, fibrinogen and prothrombin fragment 1+2 levels and decrease FactorV levels. Those changes seem to be more important with third- than second-generation OCsand are associated with an increased risk of DVT. In addition, OCs induce a resistance toactivated protein C, also observed in Factor V Leiden mutation carriers, resulting in adecreased sensitivity to the anticoagulant action of activated protein C.[13] Rosing et al.demonstrated that third-generation OCs caused a more pronounced resistance.[18] Themolecular basis of this acquired resistance is unknown, but it can be in part explained by thedecreased level of cofactors of the activated protein C. Additionally, different fibrinolyticvariables are altered by OCs (plasminogen, tissue plasminogen activator, plasminogenactivator inhibitor type I and plasmin-antiplasmin complexes), which theoretically result inincreased fibrinoloytic activity. The clinical implications of these changes are unknown.Finally, prothombotic effects of third-generation pills could be explained on the one hand bythe increase in procoagulant effect, and on the other hand by the decrease in anticoagulanteffects. These effects appear to be more important with third-generation pills than withsecond-generation ones. This is probably an example of the complexity of thepharmacological effects of steroids. Although estrogen doses are lower, third-generationprogestagens may potentiate the estrogenic effects on clotting factors, thus resulting in aprocoagulant effect. However the precise mechanism of those supposed effects remains tobe elucidated.

The risk of having an arterial problem is increased in OC users. This risk includes coronaryheart disease and stroke. Cigarette smoking and age are the main associated vascular riskfactors. The overall annual OC-attributable risk mortality in women below 35 years old isestimated at three per million users or below, rising to ten per million users annually amongsmokers.[19] Globally, the mortality risk from all other causes is around 90 per million womenof reproductive age. The annual OC-attributable incidence of vascular disease increases withage,[20] and with cigarette smoking.[2] Smoking by itself increases the arterial risk and thisincrease is over and above that observed with the use of OC use alone. The association ofOCs and cigarette smoking strongly potentiates the risk.

Myocardial infarctions (MIs) are very rare among women in the reproductive age, rangingfrom two per million in a 30-year-old woman to 20 per million in 40- to 44-year-old women.[19]

The first MI associated with the use of OCs was reported as early as 1963[21,22] suggestingfor the first time a thrombotic mechanism, related to a high dose of EE. Several subsequentstudies have shown an increased risk of MI in OC users versus nonusers. With thedevelopment of third-generation OCs, a decrease in the MI risk was expected, due to animprovement of the lipid profile. In 1999, the case-control MICA study was conducted toevaluate the occurrence of MI in women using different OCs.[23] In total, 448 women agedbetween 16 and 44 years with previous MI were matched by age with 1728 healthy controls.A total of 85% of cases had not been taking OCs in the 3 months prior to their MI. Subgroupanalysis did not show any significant difference between second- and third-generation OCs.



In addition, there was no effect of the duration of use of the OCs. In 2001, Tanis et al.compared risk of MI in second- and third-generation OCs users in a case-control study.[22]The risk of MI was twice as high in OC users compared with nonusers. A direct comparison ofOCs containing 30 µg of EE and levonorgestrel (second generation), desogestrel orgestodene (third generation) revealed a nonsignificant odds ratio (OR) of 0.5 (95%confidence interval [CI]: 0.2-1.1) in third-generation pill users versus second-generations pillusers.

In 2003, a meta-analysis of 23 studies[24] estimated an overall OR of 2.5 for current OC usersversus nonusers. Another meta analysis in 2004 pooled 14 studies showing a 1.84 OR (95%CI: 1.38-2.44) for MI in users versus nonusers.[25] Subgroup analysis showed a significantlyincreased risk with second-generation pills (OR: 1.85; 95% CI: 1.03-3.32) while the riskassociated with third-generation pills was not significant.

Ischemic strokes are very rare in healthy women in the reproductive age. The annualincidence is about six per million between the age of 20 and 24 years and rises to 16 permillion between the age of 40 and 44 years.[19]

In 2002 the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) studyanalysed five case-controlled studies, showed a relative risk of ischemic stroke in currentusers of OCs containing less than 50 µg EE of 2.2 in users compared with nonusers.[26] Thisrisk was more important in smokers. Baillargeon's meta-analysis found an increased risk ofischemic stroke in second- and third-generation OC users (OR: 2.12; 95% CI: 1.56-2.86).[25]The respective relative risks were 2.03 in third-generation OC users and 2.12 in second-generation users.

Oral contraceptives increase the overall risk of hemorrhagic stroke, in women over 35 yearsold (risk ratio [RR]: 2.2; 95% CI: 1.5-3.3).[19] The specific third-generation OCs-associatedrisk is unknown.

The evaluation of the carcinologic risk associated with various types of OCs remains unclear.The reason for this is the change of the estrogen dose and the type of progestogen in pillsduring the long follow-up necessary for this evaluation especially for breast cancer. Availabledata generally report on the global OC related risk independently of the OC generation.

Breast cancer has been evaluated in a pooled analysis of 54 epidemiologic studies. A total of53,297 women with breast cancer were compared with 100,000 controls.[27] Current OC usewas associated with a small increase in the relative risk of localized breast cancer (RR: 1.24;95% CI: 1.15-1.33). The risk declines shortly after discontinuation of OC use (RR: 1.16; 95%CI: 1.08-1.23 after 1-4 years and RR: 1.07; 95% CI: 1.02-1.13 stopping after 5-9 years). Thereis no significant excess risk of having breast cancer 10 or more years after stopping the useof OC (RR: 1.01; 95% CI: 0.96-1.05). These very reassuring elements are brought by acollaborative work that represented approximately 90% of the epidemiological information onthe topic available in 1996. Short term OC use (1-4 years) did not increase the risk of breastcancer. This meta-analysis includes six prospective and 38 retrospective studies. In the sixprospective studies, the overall relative risk of breast cancer is 1.07 ± 0.35. By the age of 50years there is no difference in the risk of breast cancer among ever users of OCs comparedwith controls. Breast cancers diagnosed in long term users are typically less advancedclinically than cancer diagnosed in nonusers, suggesting a bias of screening in OC users.

Since this important collaborative work, five main case-control or cohort studies haveevaluated the risk of breast cancer in relation to the use of OC, all of them concluded amoderate increase (RR below 1.4) or absence of increase in the risk of breast cancer.[28-32]The only exception were young women with breast cancer diagnosed before the age of 45years reporting a recent use of OCs. However, in a recent prospective cohort study

conducted in Norway and Sweden,[33] a 1.5 relative risk (95% CI: 1-2) of invasive breast



conducted in Norway and Sweden,[33] a 1.5 relative risk (95% CI: 1-2) of invasive breastcancer has been observed in women using OCs. The influence of past use of OCs on thepostmenopausal diagnosis of breast cancer has been specifically addressed by Magnussonin a case-control study conducted in women aged 50 to 74 years diagnosed with breastcancer.[34] The relative risk was 0.98 (95% CI: 0.86-1.12) and there was no correlation withthe duration of use, age at the beginning of use or time since discontinuation of OCs.

Data obtained in women bearing a very high familial or genetic risk, such as a BRCA1 orBRCA2 mutation, have also been reassuring. A large reanalysis of 52 studies showed anabsence of increased relative risk of breast cancer in women with a family history of breastcancer.[27] Grabrick et al. described an increased risk of breast cancer in women with a first-degree relative affected by breast cancer (RR: 3.6; CI: 1.5-7.2) if OCs had been used before1975, while the risk was not increased (RR: 0.9; CI: 0.2-4.5) if OCs had been used after 1975.[35] This suggests that second- and third-generation OCs have a significant advantage in thishigh-risk population. The influence of OCs in BRCA mutation carriers has been analyzed in acohort of nearly 5000 women from 11 countries.[36] In this study, the risk of breast cancer wasalso increased in BRCA1 mutation carriers if they had used OCs before 1975, before the ageof 30 years and for more than 5 years. In all other situations the risk was not increased, takinginto account that the number of BRCA2 mutation carriers was limited and did not allow clearconclusion.

Studies focused on the specific risk of different progestins and dosages of EE2 are notavailable. However, global results are largely reassuring, including in women bearing a veryhigh risk of breast cancer. There are no arguments in the literature suggesting that theincidence of breast cancer is increased in past users of OCs.

The risk of ovarian cancer appears to decline with the duration of use of OCs. Schlesselmanet al. have reported that the risk reduction increases from 41% after 4 years use to 61% after12 years' use.[37] This effect seems to persist after discontinuation of use,[38] and appears tobe correlated to high progestin potency.[39] It may be related either to the antigonadotropeeffect of the OC or to a direct effect of the progestin that remains unknown. As for breastcancer, this risk has not been specifically evaluated for third-generation OCs. In women witha BRCA1 or BRCA2 mutation, OCs do not appear to reduce the risk of ovarian cancer risk.[40]

The incidence of endometrial cancer incidence is also lower in OC users,[37] including inwomen using OCs with low doses of estrogen (30-35 µg).[41]

The use of OCs is associated with an increased risk of cervical intraepithelial neoplasia andcervical cancer.[42] This risk is correlated to the duration of use. The mechanism is unclear,since epithelial cervical cancer doesn't seem to be hormone dependent. This type of canceris mainly caused by a sexually transmitted human papilloma virus, suggesting a bias instudies showing an association between OCs and cervical cancer.

In the past few years there have been articles raising the concern that the use of OCs mayinterfere with the normal acquisition of peak bone mass in young women. Some studiesreported a negative influence of OC on the normal age-related increase in bone mass.[43,44]Another study demonstrated that OC use was associated with a lower mineral density of thespine and femoral body (BMD) relative to control subjects.[45] Two large epidemiologicalstudies suggested an increased relative risk for fractures in premenopausal women who hadused OCs compared with those who had never used OCs.[46] Furthermore, in a recentretrospective analysis of female athletes, it was found that long-term OC use was associatedwith decreased BMD of the spine and of the femoral neck, and that the initial age of usingOCs was a major determinant of spine BMD.[47] Recently, in a cross-sectional analysis,Hartard et al. found that women who had ever used OCs had significantly lower bone mass at



the femoral neck and at the tibial shaft, despite similar age, height, weight, BMI, hours ofexercise per week and calcium intake.[48]

Thus, these studies suggest a negative action of OCs on bone, particularly in young women.However, first, these studies include a limited numbers of subjects and, second, even if theeffect on BMD appears to be detrimental, the effect on the incidence of bone fracture in thispopulation still has to be demonstrated. In 2004 a WHO statement on the benefit-risk balanceof OCs from the point of view of bone health concluded in favor of the use of OCs.[49] Finally,the pathophysiological mechanism of this negative effect is not clearly understood.

Current use of OCs has shown excellent efficacy and tolerance profiles. Its use has beenbroadened to other indications.

Since its introduction, the first contraceptive pill underwent many modifications to increase itsefficacy and tolerance. Currently, second- and third-generation pills are excellentcontraceptive methods, and are currently widely offered to women as a first choice in manycountries. We have summarized data on vascular and carcinologic effects of OCs. It is veryimportant to consider that the absolute risk of these events remains very low in women in thereproductive age and prescription should not be limited to women without risk factors ( ). Thepotential effect of OCs on bone may result in BMD reduction but an increase in bone fractureshas not been reported to date.

Affinity of Progestins for the Different Steroid Hormone Receptors

ProgestinRelative binding affinity for steroid receptors (%)

PR AR ER GR MRProgesterone 50 0 0 10 100Norethisterone 75 15 0 0 0Levonorgestrel 150 45 0 1 75Norgestimate 15 0 0 1 03 ketodesogestrel 150 20 0 14 0Gestodene 90 85 0 27 290Chlormadinone Ac 67 5 0 8 0Cyproterone Ac 90 6 0 6 8Medroxyprogesterone Ac 115 6 0 29 160Nomegestrol 125 6 0 6 0Promegestone 100 0 0 3 53Drospirenone 35 65 0 6 230

The relative binding affinity (%) of the main progestins discussed in this paper for the differentsteroid receptors is indicated. These results are based on in vitro studies and bioassays.Such data are used for a primary prediction of the potential effects of a compound. Asdiscussed in the text this data may be revisited with our current knowledge of the mechanismof action of steroids.AR = Androgen receptor; ER = Estrogen receptor; GR = Glucocorticoid receptor; MR =Mineralocorticoid receptor; PR = Progesterone receptor.

Furthermore, due to a very broad prescription, OCs were used in populations with risk factors



for either vascular events or breast cancer. Data collected from these series do not suggest acontraindication in young women with noncomplicated, well-controlled Type 1 diabetes orcontrolled dyslipidemia.[50] In a similar way, as previously discussed, OCs can be used inyoung women with a genetic risk of breast cancer. This provides a well-tolerated efficientcontraception in women who already have to deal with at least one medical problem.However, two contraindications remain: hypertension (possibly with exception of thosewomen under the age of 35 years with well-controlled blood pressure and with nocomplications) and the risk of DVT.[50]

Available data do not bring arguments for a specific increase of any risk in past OCs users inthe future, except possibly for bone mineral density, although the clinical significance of thislast point has not been determined. Current use may thus not have any future implicationfrom the individual viewpoint (e.g., in terms of follow-up), neither would it imply public-healthspecific attitudes towards these women. Usual screening and care for vascular risk factors,osteoporosis risk factors (including vitamin D deficiency) as well as regular breast cancerscreening should be conducted in women reporting past OC use in the same way as in otherwomen.

Progress in hormonal contraceptives use in the future may rather come from two oppositesides: basic clinical management and sophisticated research progress.

First, a careful search for risk factors before prescription of OCs will remain a central tool toavoid severe adverse events. Second, patient education on reproductive physiology andcontraception will allow improvement of gynecological tolerance and compliance. Morespecifically, depending on the part of the world they live in, education of teenagers betweenthe age of 13 and 18 years by healthcare personnel as well as parents (teachers should notbe responsible for this information) may be useful.

With regards to research and development, new tools to detect risk factors may arise,including susceptibility screening at the genomic level or pharmacogenomic progress.Molecular pharmacology of steroids will also potentially participate in the improvement ofhormonal contraception. Understanding the pharmacology of OCs is not easy since theeffects of progestins and EE on various target tissues, target genes and risk markers arelargely interfering. During the development of the different generations of OCs, estradioldoses have decreased with the evolution of the pharmacological profile of progestins, and anunexpected increase in DVT has been observed. It has been suggested that the decrease inthe dose of progestin or the modification of the progestogen may have increased somepharmacological effects of EE on clotting factors, even when EE doses were reduced.Although the exact mechanism of this phenomenon is not known today, our currentknowledge of the mechanisms of action of steroids may bring some elements of an answer inthe future. Estrogens and progestins act via nuclear receptors to activate target genestranscription and their action is modulated by coregulator proteins (Figure 2).[51] Some ofthese coregulators (coactivators) enhance transcriptional activity while some others(corepressors) decrease it. The same coactivator may cooperate with different nuclearreceptors and in the same time modulate their specific transcriptional activity in an oppositeway.[52] In addition, PR is now known to have two main different isoforms, A and B. PRA andPRB have distinct target genes and probably interact with different coregulators.[52,53]Estrogen mineralo-corticoid and glucocorticoid receptor as well have distinct isoforms.[54,55]The final effect of a steroid binding to its specific receptor thus mainly depends on themolecular context at the target DNA region. The presence of two different steroid receptors inthe same DNA region and their specific interactions with coregulators may strongly modifythe final transcriptional effect and biological response.[56,57] Prediction of the final biologicaleffect of a steroid, in particular progestins, has been based on its known affinity for thedifferent steroid receptors ( ) and its effects in animal models. In particular, steroids exhibitinga strong affinity for the androgen receptor are expected to have more metabolic side effects.



This concept will need to be revisited in the new molecular biology context, and a newclassification of progestins may arise.

Interactions between the different steroid receptors involved in the mechanism of action oforal contraceptives. The activation of transcription of target genes and therefore induction ofcellular therapeutic or adverse events are largely interfering. The pivotal role of coregulator inthe mechanism of action is shown as the intersection between the different receptors. AR =Androgen receptor; ER = Estrogen receptor; GR = Glucocorticoid receptor; MR =Mineralocorticoid receptor; PR = Progesterone receptor.

Currently, despite a large prescription of contraceptives, the level of unwanted pregnanciesremains too high globally, suggesting difficulties in compliance.

The high prevalence of pill omissions (up to 27% within 3 months[58]) indicates the necessityof finding solutions to cope with this problem. The effect of pill omissions during oralcontraception is related to the moment in the pill cycle and the number of pills missed.[59]The other main problem is to elaborate well-tolerated hormonal contraceptives that could beused in women with known DVT risk or hypertension not willing to use IUDs.

Considering that the incidence of obesity and subsequently the number of women bearingvascular as well as carcinologic risk factors is increasing, the search for adequate andefficient alternatives is a very important target for future research. Different recentdevelopments have targeted both goals of reducing compliance failure and impact onvascular risk.

The amount of EE has been reduced to 15 µg per day. Although these associations may bebetter tolerated by women with metabolic risk factors,[60] they appear to be less well toleratedin terms of bleeding and sex life compared with a 20 µg EE-containing pill or to a vaginal ringdelivering 15 µg of EE per day.[61] The effect on bone mineral density of such low-dose EE



treatment remains to be determined.

The administration of OCs, of all the tablets containing the same active compound, withoutinterruption, is a strategy used to improve symptoms, such as bloating, dysmenorrhoea,headaches and mood fluctuations, related to the menstrual period. Such symptoms havebeen shown to be associated with a high rate of absenteeism. Available data on continuousversus noncontinuous-dosing of OCs have been analyzed recently in the Cochranedatabase.[62] Contra-ceptive efficacy and compliance were similar between groups. Bleedingpatterns were either equivalent or improved with continuous-dosing regimens. Thecontinuous-dosing group had greater improvement of menstrual-associated symptoms.Furthermore, endometrial safety is not modified with the continuous-dosing scheme.

Nonoral routes of administration, mainly transdermal and vaginal, have been developed inthe hope that nonoral delivery of ethinylestradiol might mitigate its effects on the liver, asreported with 17β-estradiol.[63] An additional benefit is that the vaginal route allows amonthly administration, and transdermal devices are renewed weekly. Unfortunately,premarketing studies on vascular risk markers have shown that both of these nonoral routesalso had negative effects, resulting in the maintenance of the same contraindications as OCs.Sitruk-Ware et al. found similar effects on hemostatic variables and estrogen-sensitive liverproteins in postmenopausal women using daily vaginal or oral 15 µg of EE.[64] These dataclearly show that the hepatic impact of EE is mainly related to the very importantpharmacological potency of EE (due to the ethinyl radical), independently of an associatedprogestin. Transdermal administration of EE[65] associated to norelgestromin, a metabolite ofnorgestimate, has been studied in two epidemiological studies. One study reported anincreased risk of DVT in users while the other study did not. Consequently, the impact of EEon liver functions appears to be independent of the route of administration and also of hepaticfirst pass. These new routes of administration are therefore thus not applicable to women withhigh vascular risk. However, they have the same excellent profile of general andgynecological tolerance and can ideally be offered to women with poor compliance.

Another way of improving vascular tolerance is the use of as-sociations of nontestosterone-derived progestins and EE (Figure 3).



Progesterone-derived progestins and classification.

The association of CPA and EE has been used for many years in women with hirsutism.CPA is a progesterone derivative with antiandrogenic properties. It is used as a safe methodof contraception in women with systemic lupus erythematosus, bearing a high risk of venousand arterial thrombosis, without increasing this risk.[66] The association of CPA with EE hasbeen reported to increase the risk of DVT in normal women[67] or in women with anincreased metabolic risk.[64] A recent analysis of all published studies demonstrated nodifference between 'conventional OCs' and the association of EE with CPA.[69] Inadolescents with polycystic ovarian syndrome, EE plus CPA compared with a second-generation OC has been shown to impair glucose tolerance and alter insulin secretion in asimilar way.[70]

A new OC-containing chlormadinone acetate (a progesterone derivative) and 20 µg EE(Belara®) has recently been brought on the market. Chlormadinone acetate (CMA) is aderivative of naturally secreted progesterone which shows high affinity for (and activity at) theprogesterone receptor. It has an anti--estrogenic effect and shows moderate anti-androgenicproperties. CMA shows high contraceptive efficacy by inhibiting ovulation.[71] In addition, itdecreases endometrial thickness and increases the viscosity of cervical mucus. Safetystudies have indicated that CMA has no clinically relevant effect on a wide range ofmetabolic parameters in normal subjects. Further studies in groups at high thromboembolicrisk have shown that CMA alone has a relative risk of 0.8, which is not considered significant.[72] These results indicate the possibility of CMA to be combined with EE in an OC with higheffective contraception properties and excellent cycle control. The specific DVT risk inwomen using this association is not yet known.



Drospirenone, associated to EE, has recently been made available as well. Drospirenone isan analogue of the aldosterone antagonist spironolactone and exhibits both progestationaland anti-androgenic activity.[73] Drospirenone-containing OCs are efficient, well tolerated,with side effects comparable to other OCs. It improves premenstrual syndrome symptoms andlight acne.[74] The risk of DVT in initiators of drospirenone containing OCs is comparablewith the risk in initiators of other OCs.[75]

In total, data available on the CPA- and drospirenone-EE combinations suggest that adverseevents such as DVT are due to the EE component, and that the same might be observed withall new associations including EE. Finally, future developments to find a hormonalcontraceptive solution for women with high vascular risk, will thus include non-EE-containingcontraceptives.

High doses of progestin alone can be administered for contraception in women havingvascular risk factors, going back to the initial pioneer concept. In European countries, thethree most used compounds for this purpose are nomegestrol acetate and pro-megestone(two 19-norprogesterone derivatives), chlormadinone acetate (CMA, a 17α-hydroxyprogesterone derivative). Conard et al. evaluated the impact of antigonadotropedoses of CMA (10 mg/day) on the recurrence of DVT in women with a previous history ofDVT and/or hereditary thrombophilia.[72] The incidence of DVT was similar in women usingcontraception with and without CMA. This retrospective study must be confirmed by aprospective study. Nomegestrol acetate is also often administered alone at antigonadotropicdoses as contraception, with a good level of vascular and metabolic tolerance.[76-80] One ofthe drawbacks of this technique is the occurrence of signs of estrogenic deprivation, such asvaginal dryness. This explains the reason why the addition of estradiol (orally, transdermal orpercutaneous) could be an efficient strategy to avoid these adverse events. In that case,estradiol is administered as an 'add back' therapy since the contraceptive effect is alreadyobtained using high doses of progesterone derived compounds. A compound associatingestradiol and nomegestrol acetate is currently under evaluation in Phase III studies[Unpublished data]. Two additional associations including estradiol valerate plus dienogestor estetrol plus desogestrel are currently under development. Since these new associationswill include oral estrogens, this method will probably be useful for women carrying metabolicfactors. However, its tolerance in women with thrombophilia or a history of DVT will have tobe evaluated. In fact, as shown by Canonico et al. in postmenopausal women, transdermalestrogen administration appears to be associated with a lower risk of DVT compared withoral administration.[63] Furthermore, a fourfold increased risk of DVT was observed in womentreated with norpregnane derivatives. However, these data obtained in menopausal womenmay not be extrapolable to young premenopausal women, and need to be confirmed in aprospective trial.

Although high-dose progesterone-derived progestins are used in European countries with areal contraceptive effect it has not been evaluated in large studies and the Pearl index is notknown.

Hence, low-dose progestin-only pills (POPs) are actually the only OCs allowed for womenwith high vascular risk. POPs act through a local action and do not constantly inhibitovulation. Their efficacy is thus limited and can be impaired if the tablet intake is not strictlycontrolled with regard to time (maximal delay 3 h). Korver et al. have recently demonstratedthat the 75 µg desogestrel-only pill (Cerazette®) could maintain ovulation inhibition after a 12-h delay in tablet intake.[79] Another solution to solve the tablet intake delay problem might benonuser-dependent new administration routes, such as implants. Those implants (Norplant®,Jadelle® and Implanon®) contain leve-norg-estel or etnogestrel. They are safe and highlyeffective.[80,81] However, the main drawback of progestin-only contraceptives, independentlyof the route of administration, is the high incidence of irregular vaginal bleeding leading todiscontinuation rates of close to 25%.[82] Breakthrough bleeding in POP users can be related



to incomplete suppression of ovarian activity or to a direct effect of progestins on theendometrium.

Different trials of coadministration of antiprogestogenic compounds (also called selectiveprogesterone receptor modulators [SPRMs]) with POP have been conducted to control thisadverse effect of progestins on the endometrium.[83] Croxatto et al. demonstrated that asequential administration of mifepristone and nomegestrol acetate could improve irregularbleedings.[84] In this study, administration of mifepristone (5 mg/day) during the first part ofthe menstrual cycle inhibited ovulation without decreasing estradiol secretion and allowedendometrial growth. In the second part of the menstrual cycle, nomegestrol acetate inhibitedovulation and regular menstruation was observed at the end of the 28 days' treatment.SPRMs are also efficient to improve bleeding problems associated with implants.[85,86]

Finally SPRMs administered alone in a continuous manner are currently evaluated asestrogen-free contraception. Daily low doses of mifepristone (≥2 mg/day) inhibit ovulation,prevent secretory transformation of the endometrium and induce amenorrhea.[87-89] Pei et al.have recently demonstrated that weekly administration of mifepistone (25 and 50 mg) alsoinhibited ovulation.[90] This weekly intake may participate in improving compliance. The useof SPRMs alone has the very important advantage of providing ovulation inhibition withoutlowering estradiol levels,[91] and may not result in estradiol deprivation symptoms or long-term deprivation consequences. However, as the effect of estradiol is unopposed, the impacton the endometrium by long-term use of SPRMs is unclear. It may result in simplehyperplasia as previously described in women treated for fibromyomas.[92] However, theobserved aspects may also correspond to class-specific modifications of the endometrium.[91,93-95] Intrauterine administration of antiprogestins has also been evaluated showingpromising bleeding patterns and histological profiles.[96] This may overcome the previouslydescribed potentially negative endometrial effect. Weekly administration, sequentialdiscontinuation or administration of progestins may be other options. Finally, vaginal routesof administration of SPRMs and progestins are currently under evaluation.[97]

Third-generation oral contraceptives (OCs) contain potent testosterone-derivedprogestagens and low doses of ethinyl estradiol. They are highly efficient and welltolerated, since the absolute risk of vascular events and breast cancer are very low inthe target population.

Efficacy is limited by noncompliance and can be improved by education and byprescription of non-user dependent means of administration.

Third-generation OCs can be proposed to most young women after screening forpersonal metabolic, vascular or carcinologic risk factors.

Indications can be extended to patients with well-controlled metabolic conditions andhigh risk for breast cancer. This has been validated during extensive use of second-and third-generation OCs.

The risk of deep vein thrombosis, uncontrolled metabolic conditions, vascular riskfactors, cigarette smoking and age of over 35 years are contraindications that remainand are not modified by the development of nonoral routes of administration of EE, norby the use of new nontestosterone-derived progestins. The current alternative(progestin-only contraception) is poorly tolerated in many women.



Acknowledgments

No writing assistance was utilized in the production of this manuscript.

Reprint Address

Nathalie Chabbert-Buffet, Obstetrics, Gynecology and Reproductive Medicine Department,Hospital Tenon, APHP and UPMC Univ Paris 06, 4 rue de la Chine, F 75020, Paris, France;and, EA 1533, Pierre et Marie Curie University Paris 6, Paris, France. [email protected]

Expert Rev of Obstet Gynecol. 2008;3(2):189-201. © 2008 Future Drugs Ltd.

Alternative solutions for oral contraception may include associations ofnontestosterone-derived progestins with estradiol, and progesterone receptormodulators.

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Third Generation COC