Tailoring Combination Oral Contraceptives to the Individual Woman

Abstract

Background:

Over the last 50 years, there has been intense interest in the type of progestin used in combined oral contraceptives (COC) in an attempt to exploit novel properties and minimize adverse events. At the same time, the dose of synthetic estrogen, ethinylestradiol, in COC pills has been reduced to minimize risks for ischemic stroke, myocardial infarction, and venous thromboembolism. New formulations, including extended-cycle or continuous-use COCs or those that use a natural estrogen, estradiol, may offer improvements over their predecessors.

Methods:

A Medline search was performed to encompass studies published since 1990 that pertain to the pharmacology of estrogens and progestins used in COCs, risks and adverse events associated with COCs, and extended or continuous-use COCs.

Results:

New progestins structurally related to progesterone and spironolactone may exhibit more selective binding to the progesterone receptor and lack androgenic adverse effects associated with progestins structurally related to testosterone. Recently, COCs containing natural (17β-estradiol) or conjugated estrogen (estradiol valerate) rather than ethinylestradiol have been developed in order to move to a more natural estrogen. Although many of the new progestins incorporated into COCs have not demonstrated the negative effects on lipid metabolism and other adverse events associated with the traditional progestins, the goal of attaining good cycle control has yet to be achieved. Extended-cycle and continuous-use regimens are now available that reduce the frequency of menses, but breakthrough bleeding remains a problem.

Conclusions:

Appropriate counseling to raise awareness of the specific characteristics of the different COC options available may optimize adherence and patient acceptability.

Introduction

Recent data suggest that in the developed world, the most frequently use form of contraception is combined oral contraceptives (COCs),¹ whereas worldwide, 9% of women aged 15–49 who are married or in a union use COCs.² The unmet need for family planning exceeds 20% for women of reproductive age who are married or in a union in more than 43 countries.² This unmet need for family planning in developing countries significantly dilutes the use of effective modern COCs. Three hundred fifty million couples, a third of all reproductive-age individuals, lack access to knowledge of the full range of family planning services.³

The primary contraceptive mechanism of action of COCs is ovulation inhibition due to suppression of the hypothalamic-pituitary axis. The progestin component of COCs exerts negative feedback on the hypothalamus and pituitary, causing inhibition of luteinizing hormone (LH) secretion and the LH surge necessary for ovulation.⁴ The estrogen component inhibits follicle-stimulating hormone (FSH) release, which in turn prevents follicular development.⁵

Significant changes have been made to COC formulations since their introduction to improve safety and tolerability while maintaining high contraceptive efficacy.⁶ The typical progestin dose has declined over time, and novel progestins have been introduced.⁶ Most COCs contain one of several progestins that differ in their relative binding affinities for the progesterone, androgen, estrogen, glucocorticoid, and mineralocorticoid receptors (PR, AR, ER, GR, and MR, respectively).⁷ Several of the new progestins closely mimic the activity of endogenous progesterone and have improved steroid receptor selectivity profiles that enhance tolerability.⁸

One consideration that impacts the apparent effectiveness of COCs is the importance of consistent use. Pregnancy that occurs during contraceptive use may be due to method failure (when the COC does not prevent ovulation but is used correctly) or user failure (when the COC is not taken correctly). Examination of this issue revealed that during typical use, the percentage of women experiencing an unintended pregnancy is about 8%, whereas during perfect use, the rate is about 0.3%.⁹

The Royal College of General Practitioners Oral Contraception Study is an ongoing study that was begun in 1968 following approximately 23,000 women who were using COCs and a similar number who did not use COCs. A recent report from this study¹⁰ showed that all-cause mortality was 12% lower in COC users than in nonusers, a significant result. They also found significantly fewer deaths among ever users of COCs from all cancers, all circulatory disease, ischemic heart disease, as well as all other diseases. An analysis of hormonal contraception and cancer risk with a more global perspective also found that there was no increase in cancer risk among users of contraceptives.¹¹ Other potential benefits of COCs unrelated to contraception are decreased menstrual bleeding, reduced premenstrual syndrome (PMS) symptoms, and dysmenorrhea.^12,13 COCs can reduce acne, as well.¹⁴

The aim of this review is to provide an overview of the differences between COCs with respect to their pharmacology, pharmacodynamics, pharmacokinetics, and administration schedule. The overarching goal is to provide information to healthcare providers to assist their patients in choosing the most appropriate COC for their individual needs.

Classification of Progestogens

Progestins can be classified according to the steroid to which they are related by chemical structure, namely, testosterone, progesterone, or spironolactone (Table 1). The most commonly used progestins in COCs are structurally related to testosterone, the first being norethynodrel, which was patented in 1954. Around the same period, developments in the chemical synthesis of C-19-norsteroids yielded the estrane norethindrone (norethisterone) and its prodrugs (lynestrenol, norethindrone acetate, and ethynodiol diacetate). The replacement of the methyl group at the 13-carbon of norethindrone by an ethyl group produced the more potent progestin norgestrel, a gonane with activity residing in its isomer levonorgestrel.¹⁵ The introduction of certain substituents at the 11-position of levonorgestrel produced progestins with substantially enhanced potency (e.g., desogestrel). Medroxyprogesterone acetate, which is structurally related to progesterone, was approved for use in 1956 as a progestin. Various modifications to its steroid nucleus yielded the compounds megestrol acetate, chlormadinone acetate, and cyproterone acetate.¹⁶

Table 1.

Compounds with Progestational Activity Used in Contraceptive Formulations

Structurally related to testosterone (19-nortestosterone derivatives)
Ethylinated
Estranes	Ethynodiol diacetate, lynestrenol, norethindrone, norethindrone acetate, norethynodrel
Gonanes	Levonorgestrel, desogestrel, gestodene, norgestimate
Nonethylinated	Dienogest
Structurally related to progesterone
17-OH pregnane derivatives
Acetylated	Chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate
Nonacetylated	Dydrogesterone
19-norpregnane derivatives
Acetylated	Nomegestrol acetate
Nonacetylated	Demegestone, nestorone, promegestone, trimegestone
Structurally related to spironolactone
	Drospirenone

Classifications were obtained from several sources.^5,7,14

Endogenous progesterone has antiestrogenic, antiandrogenic, and antimineralocorticoid properties. Progestins that are structurally related to progesterone more closely mimic the biologic activities of progesterone. Examples are the 19-norderivatives of progesterone, such as nomegestrol acetate, which exhibit more selective binding to the PR and, thus, avoid unwanted androgenic, estrogenic, glucocorticoid-like, and mineralocorticoid-like activities.^8,17 Drospirenone is derived from spironolactone, yet has pharmacodynamic properties very similar to those of progesterone.¹⁸ It is the only progestin currently available with potent antimineralocorticoid activity and moderate antiandrogen activity. Dienogest is technically classified as an estrane, although its activity is in fact closer to the pregnane group of progestins because of its antiandrogenic effects.⁷

Pharmacology of Progestogens

All progestogens bind to and activate the PR; however, their affinities vary by at least 1 order of magnitude.^19,20 Progestogen potency can be compared in vivo using the McPhail Index, which measures progestational activity, and the ovulation inhibition test, which measures antiovulatory potency. The McPhail Index measures the dose of progestin required to transform the uterine endometrium to a secretory state in immature, estrogen-primed rabbits.²¹ According to this test, the 19-norpregnane derivative trimegestone is twice as potent as subcutaneous nestorone, both of which have potencies 3–10-fold greater than that of levonorgestrel and>100-fold greater than that of progesterone.^20,22

Although the pharmacokinetic characteristics of many progestins in the plasma compartment are well characterized, there is a paucity of data relating to intracellular concentrations of clinically available progestins in target tissues.²³ This is one of the reasons why progestin binding affinities and serum progestin concentrations do not always correlate with results from in vivo bioassays or observed clinical effects. These effects may be agonistic or antagonistic, depending on whether the progestin induces or prevents receptor transactivation (Table 2). Based on this qualitative assessment, the closest mimetics to endogenous progesterone are 19-norprogesterone derivatives, nomegestrol acetate and trimegestone, and the spironolactone derivative, drospirenone.

Table 2.

Biologic Activities of Natural Progesterone and Synthetic Progestins

Progestin	Progestogenic	Antigonadotropic	Antiestrogenic	Estrogenic	Androgenic	Antiandrogenic	Glucocorticoid	Antimineralocorticoid
Progesterone	+	+	+	−	−	±	+	+
19-Nortestosterone derivatives
Lynestrenol	+	+	+	+	+	−	−	−
Norethindrone	+	+	+	+	+	−	−	−
Norethynodrel	±	+	±	+	±	−	−	−
Levonorgestrel	+	+	+	−	+	−	−	−
3-Ketodesogestrel	+	+	+	−	+	−	−	−
Gestodene	+	+	+	−	+	−	+	+
Norgestimate	+	+	+	−	+	−	−	−
Dienogest	+	+	±	±	−	+	−	−
Pregnane derivatives
Chlormadinone acetate	+	+	+	−	−	+	+	−
Cyproterone acetate	+	+	+	−	−	++	+	−
Medrogestone	+	+	+	−	−	±	−	−
Medroxyprogesterone acetate	+	+	+		±	−	+	−
Megestrol acetate	+	+	+		±	+	+	−
Dydrogesterone	+	−	+	−	−	±	−	±
19-Norpregnane derivatives
Nomegestrol acetate	+	+	+	−	−	±	−	−
Promegestone	+	+	+	−	−	−	−	−
Trimegestone	+	+	+	−	−	±	−	±
Spironolactone derivative
Drospirenone	+	+	+	+	+	−	−	−

+, Effective; ±, weakly effective; −, not effective.

From Schindler et al., 2003, used with permission of the publisher.²⁰

The pharmacokinetic properties of progestins have been well characterized (Table 3).^17,19 Most progestins are rapidly absorbed, and maximum serum concentrations (C_max) are attained within a few hours of oral administration. The elimination half-lives of progestins tend to be long, owing to their affinity for serum proteins and retention in fatty tissue.¹⁷ Although orally active, progesterone absorption is highly variable, and its elimination half-life is shorter than that of the synthetic progestins, making it an undesirable progestogen for contraceptive purposes.²⁰

Table 3.

Pharmacokinetic Properties of Progestins

Progestin	Bioavailability (%)	C_max (ng/mL)	Range t_max (hours)	T_1/2 (hours)	Fraction protein bound
Norethindrone^a,b	47–73	16 (dose 1000 μg)	1–2	7–8	61% to albumin
		6 (dose 500 μg)			36% to SHBG
		4 (dose 300 μg)			3% unbound
Levonorgestrel^a,b	100	6.0 (dose 250 μg)	1–3	9.9 (dose 250 μg)	50% to albumin
		3.5 (dose 150 μg)		13.2 (dose 150 μg)	47.5% to SHBG
		2.5 (dose 75 μg)			2.5% unbound
Etonogestrel^a,b,c	62–76	3.7 (dose 150 μg)	1.2–1.6	23.8	66% to albumin
					32% to SHBG
					2% unbound
Gestodene^a,b	87–99	7.0 (dose 125 μg)	1.4–1.9	12–24	75% to SHBG
		3.6 (dose 75 μg)
		1.0 (dose 50 μg)
Dienogest	96.2 (dose 4 mg)^a	23.4 (dose 1 mg)	2.2 (dose 1 mg)	6.5, 10.8 (dose 4 mg)^a	0% to SHBG
Chlormadinone acetate^a	∼100	NA	1–2	80.1^d	0% to SHBG
					96% to albumin
Cyproterone acetate^a	∼88	15.2 (dose 2 mg)^b	1.6^b	54^b 68.8–78.6^e	0% to SHBG
Medrogestone^b,f	NA	8.2 (dose 5 mg)	2.57	34.9	NA
Medroxyprogesterone acetate^b	NA	3–5 (dose 10 mg)	1–4	24	0% to SHBG 88% to albumin
Megestrol acetate^b,f	NA	125 (dose 160 mg)	6.3	22.3	0% to SHBG
Dydrogesterone^b	NA	NA	0.5–2.5	14–17	NA
Nomegestrol acetate^b	63	7.2 (dose 3.75 mg)	3.3	∼50	98% to albumin
Trimegestone^b,g	∼100	12–15 (dose 0.5 mg)	<0.5	12–20	NA
Drospirenone^a,e	66–76	79–84 (dose 3 mg)	1.6–1.8	31.1–32.5	95%–97% to albumin
					0% to SHBG

When coadministered with ethinyl estradiol.

Single-dose pharmacokinetics.

The active metabolite of desogestrel.

Based on a radioactive intravenous dose.

Steady-state after multiple oral dosing.

Studied in males.

When combined with estradiol.

C_max, maximal serum concentration; NA, data not available; SHBG, sex hormone-binding globulin; t_max, time to C_max; T_1/2, elimination half-life.

Data obtained from references 19, 20, 24, 25, 26.

Progestins Used in COCs

Monophasic COCs contain fixed doses of estrogen and progestin components, usually prescribed as a regimen of either 21 active pills followed by 7 placebo pills or 24 active pills followed by 4 placebo pills (Table 4). Several extended-use or continuous-use preparations have been approved recently for women who desire a decreased frequency of menses. Triphasic COCs contain varying doses of progestin or estrogen during the administration cycle and may improve bleeding profiles in women who do not have adequate cycle control with monophasic COCs.

Table 4.

Composition of Popular Combination Oral Contraceptives in European Union and United States

Progestin dose	Estrogen dose	Phase	Dosing	Efficacy PI	Breakthrough bleeding Duration (days)	Incidence
Norethindrone 0.4 mg	EE 35 μg	Monophasic	21 active pills+7 placebo	NA	NA	Over a 3-year period, 8%²⁷
Norethindrone 1 mg	EE 20 μg	Monophasic	24 active pills+4 placebo	1.82²⁸	0.95 (intracyclic); 18.6 (total bleeding/spotting days for cycles 2–6)²⁸	NA
Levonorgestrel 0.15 mg	EE 30 μg	Monophasic extended	84 active pills+7 placebo	0.6²⁹	12 (cycle 1), 4 (cycle 4)²⁹; after 1 year of use, 5 (cycle 1), 2 (cycle 3)³⁰	NA
Levonorgestrel 0.15 mg	EE 30 μg	Multiphasic extended	84 active pills+7 pills EE 10 μg only	0.78³¹	14 (cycle 1), 8 (cycle 4)³¹	NA
Levonorgestrel 0.09 mg	EE 20 μg	Monophasic continuous	No placebo	1.26³²	NA	20% by month 13³²
Desogestrel (DSG) (varying dose)	EE 25 μg	Multiphasic	7 pills EE/DSG 0.1 mg7 pills EE/DSG 0.125 mg	0.51³³	17.8 for 90-day reference period (mean number of episodes, 3.8)³³	Over 6 cycles: 11.0% BTBS; 3.5% BTB; 7.9% BTS³³
			7 pills EE/DSG 0.15 mg
			7 pills ferric oxide only
Desogestrel 0.15 mg	EE 20 μg	Multiphasic	21 active pills+2 placebo+5 pills EE 10 μg only	1.02³⁴	BTB, 2.7; BTS, 2.9³⁴	Over 18 cycles: intermenstrual bleeding, 12%; BTB, 3.5%; BTS, 8.9%³⁴
Norgestimate (NRG) 0.25 mg	EE 35 μg	Monophasic	21 active pills+7 placebo	0.25³⁵	NA	Over 6 cycles: BTB, 3%; BTS,4%^35,36
Norgestimate (varying dose)	EE 35 μgEE 25 μg	Multiphasic	7 pills EE/NRG 0.18 mg7 pills EE/NRG 0.215 mg	NA2.36	BTS, 3.1 per cycle; BTS, 3.7 per cycle³⁷	Over 3-4 cycles: BTB/BTS 14.4% BTB/BTS 17.2%³⁷
			7 pills EE/NRG 0.25 mg
			7 placebo
Gestodene (varying dose)	EE (varying dose)	Multiphasic	6 pills EE 30 μg+gestodene 50 μg	0.05³⁸	NA	Over 24 months: intermenstrual bleeding, 2.2%; over 6 months: BTB, 1.5%; BTS, 7.6%; BTB+BTS, 0.9%³⁸
			5 pills EE 40 μg+gestodene 70 μg 10 pills EE 30 μg+gestodene 100 μg
Dienogest (DNG) 2 mg	EE 30 μg	Monophasic	21 active pills+7 placebo	NA	NA	NA
Chlormadinone acetate 2 mg	EE 30 μg	Monophasic	21 active pills+7 placebo	0.04^a	NA	Month 1: BTB, 2.9%; BTS, 18.3%
				0.4^b		Month 6: BTB, 1.0%; BTS, 2.7%
						Month 12: BTB, 0.1%; BTS, 0.7%.³⁹
Cyproterone acetate 2 mg	EE 35 μg	Monophasic	21 active pills	NA	NA	NA
Drospirenone 3 mg	EE 30 μg	Monophasic	21 active pills+7 placebo	0.070–0.407,^a,40,41 0.71^c,41	1.8–3.3⁴²	Cycles 2–6: intermenstrual bleeding, 21.0%; cycles 2–12: intermenstrual bleeding, 30.6%⁴¹; cycles 2–13: BTB without spotting, 1%; BTBS, 3%⁴⁰; cycles 2–13: BTBS, 4.75–10.4%⁴²
Drospirenone 3 mg	EE 20 μg	Monophasic extended	24 active pills+4 placebo	0.72,^a 1.29^b,43		≥86% experienced 3–5 BTB/BTS episodes in the 90-day reference period⁴³
Dienogest (varying dose)	Estradiol valerate (EV) (varying dose)	Multiphasic	2 pills EV 3 mg5 pills EV 2 mg+DNG 2 mg17 pills EV 2 mg+DNG 3 mg	0.42⁴⁴	NA	10%–18%⁴⁴
			2 pills EV 1 mg
			2 placebo

Corrected, method failure.

Unadjusted.

Corrected for condom use.

^dApproved for use in Europe only.

PI=Pearl Index and is defined as the expected number of unintended pregnancies per 100 women years of exposure; BTB, breakthrough bleeding; BTS, breakthrough spotting; EE, ethinyl estradiol.

Norethindrone and related progestins

Norethindrone is often formulated as norethindrone acetate, which is rapidly converted to the parent compound in vivo.¹⁹ Norethindrone binds to the AR and displays androgenic activity. Norethindrone is used in a number of monophasic COC preparations, including those with a shortened hormone-free interval (24/4 regimens).

Levonorgestrel

Levonorgestrel is the progestin component in the first COC pill approved by the U.S. Food and Drug Administration (FDA) for continuous daily use throughout a 1-year period.⁴⁵ Levonorgestrel is rapidly and extensively absorbed after oral administration.¹⁹ Although levonorgestrel is one of the most potent orally active progestins, this molecule is an agonist at the AR and has androgenic activity at high dosages.²⁰ Levonorgestrel is used in several monophasic (21/7) low-dose estrogen COCs and in two extended-cycle COC regimens, which are intended to produce four menstrual intervals per year.^46,47

Norgestimate, desogestrel, and gestodene

The progestins norgestimate, desogestrel, and gestodene are generally regarded as metabolically neutral regarding effects on lipid and carbohydrate metabolism.⁵ Norgestimate is a prodrug: following oral administration, it is rapidly absorbed and almost completely converted to levonorgestrel-3-oxime (norelgestromin) and other progestationally active metabolites (including levonorgestrel) within 5 hours postdose.⁴⁸ The progestational activity of desogestrel is mediated by its metabolite, etonogestrel.⁴⁹ Unlike progesterone, etonogestrel has no glucocorticoid-like activity and does not bind to the MR.²⁰

Gestodene is absorbed without modification.^20,50 Extensive binding to sex hormone-binding globutin (SHBG) explains the low rate of gestodene clearance and elevated plasma concentrations relative to other progestins when coadministered with ethinyl estradiol.¹⁹ Gestodene is approximately three times more potent than levonorgestrel for the PR but displays similar affinity for the AR.⁷ It has affinity for the GR and MR and, therefore, may not be as selective as desogestrel.^7,20 Norgestimate and desogestrel, in conjunction with ethinyl estradiol (EE), are available as monophasic and multiphasic COCs. Gestodene is currently available for contraceptive use in Europe but not the United States.

Dienogest

Dienogest is an antiandrogenic progestin. Similar to levonorgestrel and norethindrone, dienogest differs from progesterone by having no glucocorticoid-like or antimineralocorticoid activity.²⁰ Dienogest, in combination with EE, provides good bleeding control.⁵¹ A COC containing dienogest and estradiol valerate has recently been approved in Europe and in the United States.

Medroxyprogesterone acetate and related progestins

The functional group located at the 17-position of their respective steroid nuclei renders medroxyprogesterone acetate, chlormadinone acetate, megestrol acetate, and cyproterone acetate resistant to first-pass hepatic metabolism.^16,20 None of these progestins bind to SHBG, but they do bind extensively to albumin. Chlormadinone acetate (and its metabolite 3-hydroxychlormadinone acetate) and cyproterone acetate are excreted slowly and have potent antiandrogenic activity.²⁰

Nomegestrol acetate

Nomegestrol acetate is a 19-norprogesterone derivative²⁴ that is rapidly absorbed after oral intake and has a long half-life, which may simplify management if a dose is missed. Nomegestrol acetate does not have androgenic activity and has been shown to demonstrate antiandrogenic effects. Nomegestrol acetate has been shown to have no effect on angiotensinogen.⁵²

Drospirenone

Drospirenone is a structural analog of the aldosterone antagonist, spironolactone,¹⁸ with a steroid receptor selectivity profile similar to that of progesterone.²⁰ Unlike progesterone, drospirenone does not interfere with glucocorticoid-mediated processes.^20,53 Drospirenone is used in combination with EE in a standard strength COC (30 μg EE) pill and a low-dose COC pill (20 μg EE).^18,54,55 The drospirenone-containing COC pill offers good cycle control, with rates of intermenstrual bleeding similar to those associated with the desogestrel-containing COC pill. The low-dose formulation is also approved for the treatment of acne vulgaris of moderate severity and premenstrual dysphoric disorder in the United States.⁵⁶

Adverse Effects and Risks of Progestins in COCs

Bleeding patterns

Abnormal or unscheduled bleeding is a common problem associated with COC use, especially during the first few months (Table 4).⁸ It is an area of concern for women that can impact acceptability, particularly when adequate counseling is not provided. Bleeding irregularities in one study were cited as the adverse effect leading to the highest rate of discontinuation.⁵⁷

One of the advantages associated with long-term use of COCs is good cycle control. Although the progressive reduction in EE dosage over the last 50 years has improved safety and tolerability of COCs, concerns have been raised about a potential untoward effect of reduced EE dosages on bleeding patterns. The hypothesis was tested in a meta-analysis of randomized controlled trials (RCTs).⁵⁸ Compared with COCs containing>20 μg of EE, several COCs containing≤20 μg of EE were associated with high rates of early trial discontinuation (overall and due to such adverse events as irregular bleeding) as well as increased risk of bleeding disturbances.

A meta-analysis of 22 RCTs revealed that the type of progestin and dosing regimen used may also affect cycle control.⁵⁹ Women receiving levonorgestrel were less likely to discontinue therapy prematurely than were their counterparts receiving older progestins (i.e., norethindrone, ethynodiol diacetate, lynestrenol, or norethynodrel) (relative risk [RR] 0.79, 95% confidence interval [CI] 0.69-0.91). This may have been attributable to the better cycle control evident in women using levonorgestrel compared with older progestins for both monophasic (RR 0.69, 95% CI 0.52-0.91) and triphasic (RR 0.61, 95% CI 0.43-0.85) preparations.

Thromboembolism

It is well established that COC users have an increased risk of venous thromboembolism (VTE) relative to nonusers, but definitive statistics are largely dependent on study methodology.^60

–63 A thorough literature analysis revealed two levels of VTE incidence rates among women of reproductive age, one based on community and cohort studies (3.8–13.5 cases per 10,000 woman-years) and a lower incidence found in database studies (0.7–3.8 cases per 10,000 woman-years).⁶¹ These rates of VTE background incidence are higher than reference figures (0.5–1 VTE per 10,000 woman-years) often used in the comparison with users of hormonal contraception.⁶¹ Nevertheless, evidence now indicates that high EE doses (i.e.,>50 μg vs. 30–40 μg and 30–40 μg vs. 20 μg) are associated with increased VTE risk relative to lower EE doses.⁶³ If one accounts for the duration of use, a reduction in EE dose from 30–40 μg to 20 μg for COCs containing desogestrel or gestodene significantly reduced the risk of VTE by 18% (95% CI 7-27).⁶³

As the dose of estrogen has been substantially reduced over the last five decades, the role of progestins in the epidemiology of VTE has been scrutinized. A study in 1995 indicated that COC pills containing one of the newer progestins, gestodene or desogestrel, were associated with a higher risk of VTE than COC pills containing the traditional progestin levonorgestrel, and this influenced physician prescribing.⁶⁴ However, there is some evidence that these data were confounded by such factors as selection bias.^65
–67

The question has been partly resolved, however, by results of the European Active Surveillance Study (EURAS),⁶² which followed 58,674 new COC users for 142,475 woman-years. The study was designed and powered to demonstrate possible differences between drospirenone-containing COCs, levonorgestrel-containing COCs, and other COC formulations regarding VTE risk. As a point of reference, a tentative estimate of VTE risk in nonpregnant nonusers in this study was 2.3 events per 10,000 person-years (5 events). The incidence of VTE in the drospirenone cohort was 9.1 events per 10,000 person-years (26 events) compared with 8.0 events per 10,000 person-years (25 events) in the levonorgestrel cohort. Cardiovascular outcomes using Cox regression analysis yielded similar hazard ratios (HRs) for drospirenone-containing COCs vs. levonorgestrel-containing and other COCs for VTE (1.0 vs. 0.8, upper 95% CI 1.8 and 1.3) and for arterial thromboembolism (0.3 vs. 0.3, upper 95% CI 1.2 and 1.5), suggesting that the drospirenone-containing COC did not increase VTE risk compared with the other COCs tested.⁶²

These data were complemented to some extent by the results derived from the Danish national follow-up study,⁶³ which estimated the incidence of VTE in users of COCs containing drospirenone to be 7.83 events per 10,000 person-years. The VTE incidence associated with COCs containing levonorgestrel was 5.47 events per 10,000 woman-years, lower than that estimated in the EURAS study.^62,63 As a result, there was a higher risk of VTE in users of COCs containing drospirenone than those containing levonorgestrel (adjusted rate ratio 1.64, 95% CI 1.27-2.10). The Danish national follow-up study reported a higher risk of VTE in users of COCs containing desogestrel (adjusted rate ratio 1.82, 95% CI 1.49-2.22), gestodene (adjusted rate ratio 1.86, 95% CI 1.59-2.18), and cyproterone acetate (adjusted rate ratio 1.88, 95% CI 1.47-2.42) relative to users of COCs containing levonorgestrel, consistent with most other findings but not all.^{62,68

–76} The registry linkage design of this study precludes drawing clinical recommendations. Therefore, prospective RCTs are warranted to formally evaluate this issue.

Based on this discussion of thromboembolism, we believe that the incidence of thromboembolism varies with the population being studied, but the dose of the estrogenic component clearly increases the risk in users and is correlated with the incidence of VTE. The role of the progestogen component in increasing the risk of VTE is unclear.

Hemostasis

Progestins, when used alone, have no or minimal impact on hemostatic parameters.⁷⁷ Some EE/progestin combinations accelerate coagulation and fibrinolysis, which is mediated primarily via EE-induced synthesis of hepatic proteins.⁷⁸ Progestins with androgenic properties (e.g. levonorgestrel) appear to counteract the effects of EE on clotting factors.⁷⁸ In theory, COC formulations containing newer progestins and natural estrogen (which has less impact on liver metabolism than EE) should have a neutral effect on clotting factors. In vitro studies have examined the interactions of a series of progestins on 17-beta estradiol (E₂)-induced nitric oxide (NO) mediated inhibition of platelet aggregation by endothelial cells.^79,80 Some progestogens (e.g., progesterone and medroxyprogesterone acetate) reduced the beneficial actions of E₂ on NO formation, whereas others (e.g., nomegestrol acetate and levonorgestrel) did not negate this effect.

Lipid and carbohydrate metabolism

Coadministration of EE with 19-nortestosterone-derived progestins attenuates or reverses the beneficial effects of estrogen on the high-density lipoprotein cholesterol (HDL-C)/low-density lipoprotein cholesterol (LDL-C) ratio.⁸¹ Endogenous progesterone and some of its 19-norprogesterone derivatives that do not have androgenic activity do not adversely affect plasma lipid levels.⁸² Monophasic or polyphasic combinations of EE and desogestrel did not have deleterious effects on serum lipoproteins in one clinical study.⁸³ An increasing HDL-C/LDL-C ratio was associated with use of COCs containing EE 30 μg plus norgestimate, gestodene, or drospirenone in other studies.^84
–86 A similar comparison is also observed for serum triglycerides (a rise of 47% with a COC pill containing EE 30 μg plus drospirenone 3 mg vs. no change for EE 30 μg plus levonorgestrel 150 μg).⁵⁴ The clinical outcomes of these progestin-induced changes in lipids on absolute cardiovascular risk is not known.

The androgenicity of progestins may also influence carbohydrate metabolism.⁸² However, findings from systematic reviews indicated that hormonal contraceptives had only a limited effect on carbohydrate metabolism in healthy women as well as those at risk for diabetes due to overweight⁸⁷ and that only the high-dose COCs slightly impaired glucose homeostasis in women with diabetes mellitus type 1 and type 2.⁸⁸

Estrogens in COCs

Pharmacokinetics and pharmacodynamics

E2 is the major estrogen produced by the ovary and the most potent. Although micronized E₂ is orally active, only approximately 5% is systemically bioavailable because of enterohepatic recycling and first-pass metabolism to estrone in the intestinal tract and liver.^89,90 Only 1% of E₂ in the blood circulates as unbound steroid, with 40% bound with high affinity to SHBG and the rest loosely bound to albumin.⁹¹ Addition of an ethinyl group at the 17-carbon of E₂ produces EE, which prevents metabolic inactivation and thus enhances estrogenic potency and estrogenic activity in the body.⁸⁹ EE was approximately 600 times more potent in stimulating SHBG binding capacity and approximately 200 times more potent in stimulating serum FSH and serum angiotensinogen than E₂.⁹² In general, an E₂ dose of 1–2 mg provides similar systemic exposure to estrogen as does an EE dose of 5–10 μg, based on a number of estrogenic parameters, including binding affinity.^92
–94

ER_α and ER_β are distributed throughout the body. In humans, both ER subtypes are found in uterine tissues; however, ER_α is expressed primarily in the uterus, liver, kidney, and heart, whereas ER_β is expressed principally in the bladder and the central nervous system.⁹⁵ ER_α and ER_β are both expressed in bone, breast, and specific brain regions. Physiologic responses to E₂ are the result of actions at both receptor subtypes, as ER_β can modulate and counteract the activity of ER_α to a significant extent.⁹⁵ Although EE and E₂ have almost the same affinity for ER_α, EE has approximately 3 times lower relative binding affinity and relative agonistic activity than E₂ for the ER_β receptor.⁹⁶ When their unique pharmacokinetic profiles are also considered, it is clear that administration of E₂ and EE can have different biologic effects.⁹⁷

Rationale for COC containing natural estradiol

Most modern COCs contain EE doses between 20 μg and 35 μg. This dose range is significantly reduced from the first marketed COCs, and as a result, cardiovascular risk and EE-related adverse effects (e.g., breast tenderness, nausea, headaches) have declined considerably. Nevertheless, COCs containing EE are not tolerated by some women and constitute an unacceptable health risk in others. The presence of the ethinyl group in synthetic steroidal compounds may be responsible for induction of metabolic changes in the liver that may affect risk for cardiovascular disease.⁹⁸ Oral EE administration is associated with increased production of certain procoagulant factors, whereas oral E₂ is not.^94,98 The trend away from the use of synthetic estrogens is increasingly evident for these reasons. However, previous attempts to include E₂ in a COC were largely unsuccessful owing to the high incidence of bleeding irregularities.^99,100

Results from two recent, randomized, open-label, dose-ranging, phase II studies indicated that E₂ (in the form of estradiol valerate) plus dienogest administered as a novel four-phasic regimen provides efficient ovulation inhibition with an acceptable bleeding profile (Table 4).¹⁰¹ A phase III trial in 798 women reported that the dienogest/estradiol valerate COC had an acceptable bleeding profile similar to the comparator and appears to have equal clinical contraceptive efficacy.¹⁰² A second product containing nomegestrol acetate (2.5 mg) plus E₂ (1.5 mg) has been developed as a monophasic COC (24/4 regimen) and has been shown to completely inhibit ovulation in menarchal women. In a randomized six-cycle study, nomegestrol acetate/E₂ provided robust ovulation inhibition with effects on the ovaries, endometrial thickness, and cervical mucus at least similar to those of drospirenone/EE (3/mg/30 μg) and produced less stimulation of SHBG than drospirenone/EE.^103,104 Nomegestrol acetate/E₂ had significantly fewer adverse effects on parameters of blood coagulation and fibrinolysis than a levonorgestrel/EE (100 μg/20 μg) regimen.¹⁰⁵

Extended Cycle and Continuous-Cycle Strategies

Extended-cycle and continuous-cycle COCs are now available for women who desire a decreased frequency and duration of menses (Table 4).¹⁰⁶ These preparations address the concept that monthly menses during the pill-free period of a 21/7 regimen are natural and needed. The endometrium does not accumulate in women receiving COCs, as ovulation does not take place, and the progestogens inhibit estrogen activity and endometrial growth. These preparations are as effective in preventing pregnancy as traditional 21/7 COCs, although their long-term safety profile has yet to be established. The main drawback associated with extended-cycle and continuous-cycle COCs relative to traditional 21/7 COCs is an increased frequency of unscheduled and unanticipated breakthrough bleeding and spotting.¹⁰⁶

The latest option is a continuous daily regimen containing EE 20 μg plus levonorgestrel 90 μg taken for 1 year. Randomized controlled data and a meta-analysis indicate that this form of contraception is effective and safe,¹⁰⁷ but the convenience of developing amenorrhea at 1 year must be balanced by the potential for unscheduled bleeding and spotting, particularly during the first 3–6 months of use.³²

Conclusions

Currently available COCs are highly effective and safe for eligible women but may present an unacceptable health risk in women predisposed to cardiovascular disease or liver disease. COCs are not recommended in women who are breastfeeding, who smoke and are over the age of 35, or have diabetes, migranes, or untreated high blood pressure or a history of thromboembolic disease. COCs can be used in otherwise healthy women until menopause, after weighing the individual risks and benefits.^{108

–114}

Selection of the most appropriate COC for an individual takes into account many factors, including the EE dose and type of progestin. As there are important pharmacodynamic and pharmacokinetic differences between the progestins, it is possible to individualize treatment according to patient needs and preferences. Nevertheless, in some instances, trial and error may be required to identify the appropriate COC.

The 19-norprogestins are similar to progesterone in terms of adverse effects and may be useful for women who do not tolerate the 19-nortestosterone derivatives. Indeed, new formulations containing progestin components that are closer in activity to progesterone are gaining popularity, as many of them are devoid of residual androgenic, glucocorticoid-like, and mineralocorticoid-like effects. For instance, women who have acne or hair disorders may derive benefit from a COC containing an antiandrogenic progestin, such as chlormadinone acetate, cyproterone acetate, or dienogest. The physician should be aware of the fact that all COCs have potential to reduce the incidence of acne. Drospirenone-containing COCs may also be preferred in women with premenstrual dysphoric disorder, with the understanding that this compound has the premenstrual dysphoric disorder indication only in the United States. The need to mitigate unscheduled bleeding may be best accomplished with use of a COC containing levonorgestrel, gestodene, or drospirenone.

The most significant development in the 50-year history of oral COCs is the availability of pills containing 17β-estradiol, the endogenous ovarian hormone. The rationale for E₂ is to improve on the tolerability profile associated with low-dose EE, particularly with respect to VTE, which will need to be confirmed by large epidemiologic studies.

One of the main challenges of the new COCs is the attainment of good cycle control. Several novel regimens are now available that reduce menses, but unscheduled bleeding remains a problem that occurs most often during the first few months of treatment. Appropriate counseling about possible changes in bleeding patterns may optimize adherence and patient acceptability.

In conclusion, the wide selection of COCs now available means that clinicians can tailor therapy to meet the requirements of the women coming to them for contraceptive care. Taking into account the woman's age and lifestyle, as well as other medical conditions, in the discussion of contraceptive choice, more women may choose to use COCs instead of less reliable forms of barrier or spermicidal contraception.

Footnotes

Acknowledgments

We thank Alex Loeb, Ph.D., and Malcolm Darkes, Ph.D., of Evidence Scientific Solutions, Philadelphia, Pennsylvania, for editorial support, which was funded by Schering Corp., a division of Merck and Co. The authors received no compensation or honoraria in association with this article.

Disclosure Statement

D.F.A. has been a consultant for Agile Therapeutics, Bayer Healthcare, Merck (formerly Schering Plough, Organon), Novo Nordisk, Warner Chilcott, and Wyeth Laboratories (now Pfizer). He has received research support from Bayer Healthcare, Duramed, Merck (formerly Schering Plough, Organon), and Wyeth Laboratories (now Pfizer) and has received direct lecture fees from Bayer Healthcare, Merck (formerly Schering Plough, Organon), and Wyeth Laboratories (now Pfizer).

I.L.L. reports no competing financial interests.

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