Contraception 87 (2013) 706 – 727

Review article

Ethinyl estradiol and 17β-estradiol in combined oral contraceptives:

pharmacokinetics, pharmacodynamics and risk assessment☆
Frank Z. Stanczyk a,⁎, David F. Archer b , Bhagu R. Bhavnani c
a
Departments of Obstetrics and Gynecology and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles,
CA 90033, USA
b
Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA
c
Department of Obstetrics and Gynecology, University of Toronto, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada
Received 30 October 2012; revised 25 December 2012; accepted 25 December 2012

Abstract

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been
ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol
(EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes
of COC treatment. Previous attempts to use endogenous 17β-estradiol (E2) instead of EE were limited primarily by poor cycle control. The
recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These
formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the
pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.
© 2013 Elsevier Inc. All rights reserved.

Keywords: 17β-Estradiol; E2; Combined oral contraceptive; COC; Ethinyl estradiol; EE

1. Introduction ception, including COCs, intrauterine devices/intrauterine

Combination oral contraceptives (COCs) have enabled
millions of women to avoid unintended pregnancies since
their introduction in 1960. Today, women have unprece-
dented choices with regard to reversible hormonal contra-
☆ estrogens: mestranol, ethinyl estradiol (EE), estradiol
Notes: Frank Z. Stanczyk is a consultant for Agile Therapeutics and
Merck & Co., Inc. (formerly Schering Plough, N.V. Organon), and has
consulted for Bayer Healthcare and Shionogi. David F. Archer is a
consultant for Agile Therapeutics; Bayer Healthcare; CHEMO; Depomed;
HRA Pharma; Merck & Co., Inc.; Shionogi; Warner Chilcott; Watson
Pharmaceuticals and Wyeth Laboratories (now Pfizer Inc.). He has received
research support from Bayer Healthcare; Duramed; Merck & Co., Inc.;
Warner Chilcott; Watson Pharmaceuticals and Wyeth Laboratories (now
Pfizer Inc) and has received direct lecture fees from Bayer Healthcare;
Merck & Co., Inc.; and Wyeth Laboratories (now Pfizer Inc.). Bhagu
Bhavnani has nothing to disclose.
⁎ Corresponding author. USC Keck School of Medicine, Reproductive
Research Laboratory, Livingston Research Building, 1321 North Mission
Road, Los Angeles, CA 90033, USA. Tel.: +1 323 226 3220; fax: +1 323
226 2850.
E-mail address: fstanczyk@socal.rr.com (F.Z. Stanczyk).
0010-7824/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.contraception.2012.12.011
systems, long-acting hormone-releasing implants, weekly
transdermal patches and monthly vaginal rings. Despite the
number of contraceptive options available to women, COCs
remain the most popular form of reversible hormonal birth
control, especially in North America and Europe.
Several progestins are used currently in COC formula-
tions in the United States. Each is combined with one of four
valerate (E2V) and 17β-estradiol (E2). The majority of the
past and current COCs contain EE.The initial presence of an
estrogen in COCs was accidental owing to the presence of
the contaminant, mestranol, produced during the synthesis of
the progestin norethynodrel [1,2]. Mestranol was later shown
to be a prodrug for EE, and it is rarely used in COCs today.
The estrogenic component provides cyclic stability when
combined with progestins in COCs and enhances the
suppressive effect of the progestin on the hypothalamic–
pituitary–ovarian (HPO) axis.
Although EE and COCs are safe, there are concerns
regarding adverse events (AEs) and side effects, especially in
smokers. Concerns associated with COCs include cancer
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
(particularly breast cancer), blood clots, heart attacks, stroke,
weight gain and loss of libido. Side effects include
breakthrough bleeding, breast tenderness, nausea, headache
and mood changes.
Initial reductions in EE dose (from N 50 mcg to 30 mcg)
were associated with decreased cardiovascular risk [3,4].
Although further reductions in the total dose of EE (from 30
mcg to b 20 mcg) in COCs may theoretically be more
tolerable, data from existing randomized controlled trials do
not have enough statistical power to enable the detection of
differences between COCs for these rare AEs [5]. Nonethe-
less, reductions in the dose of EE to ≤ 20 mcg have led to
fewer AEs and side effects [5], yet room for improvement
remains. Low-dose COCs result in higher rates of bleeding
irregularities, and women receiving COCs with lower doses
of EE are more likely to discontinue treatment, possibly
leading to higher rates of unintended pregnancy.
Since the late 1970s, researchers and pharmaceutical
manufacturers have investigated replacing EE with E2 or
E2V in COCs to improve their safety and tolerability profiles,
especially with regard to cardiovascular events, hemostatic
parameters and lipid metabolism. Until recently, efforts to
incorporate physiologic (endogenous) sex steroids into
COCs have largely failed owing to poor cycle control,
especially when E2 was administered as part of a monophasic
or biphasic regimen [6–12].
The first COC with E2V, Femilar®, was a biphasic 21-day
regimen containing a combination of E2V (1 mg) and
cyproterone acetate (1 mg) taken for 10 days, plus E2V (2
mg) and cyproterone acetate (2 mg) taken for 11 days [13].
Femilar, first marketed in Finland in 1993, showed good
efficacy, but bleeding profiles were more irregular than those
of COCs containing EE [14]. There are two possible
explanations for these bleeding problems: (a) the proges-
tin-stimulated endometrial 17β-hydroxysteroid dehydroge-
nase (17β-HSD) rapidly converts E2 to estrone (E1), which
cannot maintain stable endometrial proliferation, and (b)
progestins reduce nuclear E2 receptor concentrations and
thereby decrease nuclear E2 bioavailability and estrogenic
endometrial proliferation. Thus, it appears that the decrease
in endometrial proliferation depends on the antiestrogenic
effect of the progestin component. Due to this finding, new
formulations combining E2 with progestins with lower
antiestrogenic potential have been developed to reduce
endometrial breakdown [15,16]. One formulation consists of
a combination of E2V (1, 2 or 3 mg) and the progestin
dienogest (2 or 3 mg) used in a multiphasic regimen [17–20].
The other formulation consists of E2 (1.5 mg) combined with
nomegestrol acetate (NOMAC; 2.5 mg) in a monophasic
daily regimen [21–25]. The long-term potential benefits and
adverse effects of these E2-based COCs remain to be
established due to their recent introduction.
The aims of this review are (a) to provide a comprehen-
sive background on the biochemistry and physiology of E2,
and the pharmacology of both E2 and EE, including their
pharmacokinetics and pharmacodynamics, and (b) to discuss
707
and compare whenever possible the advantages and
disadvantages of using these estrogens.
2. Materials and methods
An extensive literature review was performed using the
MEDLINE/PubMed database. Additional resources were
identified using reference lists of the obtained articles as well
as pertinent book chapters on the subjects of E2 and EE.
Although we focused on the more recent literature, no limit
on year of publication was used in this review.
3. Biochemistry of endogenous (physiologic) E2 in
premenopausal women
3.1. Formation and secretion of hormones during the
menstrual cycle
The normal reproductive years of healthy women are
characterized by several complex physiological changes that
occur on a monthly basis. Some of these changes involve the
secretion of the hypothalamic hormone gonadotropin-
releasing hormone (GnRH); the anterior pituitary hormones
follicle-stimulating hormone (FSH) and luteinizing hormone
(LH); and the ovarian hormones E2, E1 and progesterone.
This monthly rhythmic pattern of the menstrual cycle
consists of four distinct phases that include menstruation
and the follicular (proliferative), ovulatory and luteal
(secretory) phases. Since this review deals with the use of
E2-based COCs, the biosynthesis and metabolism of
endogenous E2 and its potential contribution to the E2
derived from the COCs are discussed. To better understand
this, the formation of E2 and its regulation during the normal
menstrual cycle are briefly outlined.
The menstrual cycle is highly regulated by a delicately
balanced interplay of the HPO axis, as shown schematically
in Fig. 1 and discussed briefly below. As the circulating
levels of progesterone and estrogen from the previous cycle
fall, menstrual bleeding occurs. The mean length of the cycle
is 28 (range, 21–35) days. The first 13 to 14 days comprise
the follicular phase with ovulation occurring on approxi-
mately days 14 to 16, and the last 14 days comprise the luteal
phase. The variability in most menstrual cycles is due to the
length of the follicular phase. Falling or low levels of E2 and
progesterone during menstruation result in the secretion of
GnRH, which in turn signals the pituitary to secrete
increasing levels of FSH, followed by increasing levels of
LH. These changes result in the initiation of growth of new
ovarian follicles and ovulation; the sloughing off of the
endometrium formed during the previous cycle (menstrua-
tion) usually lasts for 3 to 7 days. The developing ovarian
follicles start to produce increasing amounts of E2 that, in the
beginning of the new ovarian cycle, do not have a high
enough level in the blood to inhibit the secretion of FSH and
LH. Although both FSH and LH are required for ovarian
708 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727

fertilization of the ovum released during ovulation occurs

and pregnancy has been initiated, in which case it continues
Higher
Highe to produce large amounts of progesterone until the placenta
Brain
ain Cente
Center
takes over the production of progesterone approximately
± ve
Hypothalamic 7–8 weeks after conception.
GnRH
Concurrent with the ovarian secretion of E2, progesterone
and a number of other steroid hormones, there are peptides
E 2 /P Positive/negative feedback

± ve such as inhibin, follistatin and activin that have been shown

Pituitary Gonadotrope to play a role in both the negative and positive feedback
mechanisms discussed above. The endocrinology of the
FSH LH
menstrual cycle has been recently reviewed [35]. The
steroidogenic pathway in the ovary is regulated by LH and
Ovary FSH and will be discussed in a subsequent section.
Follicle Corpus
Ovulation
Luteum 3.2. Biosynthesis of steroid hormones by the human ovary

E2 E2 + P
During the premenopausal reproductive years, the human
ovarian follicle and the corpus luteum produce the sex
steroid hormones E2, progesterone and testosterone, by the
Normal COCs well-established classical pathway of steroidogenesis start-
Targets ing from cholesterol or from acetate, which is converted to
cholesterol by multiple reactions. Since this pathway has
Reproductive Tract Withdrawal
Menstrual Fallopian Tubes Bleeding been extensively reviewed [36–38], only the biosynthetic
Bleeding
Endometrium Prevention of pathway pertaining to the human ovary, from cholesterol to
Cervical Mucus Pregnancy
the sex steroids, is discussed briefly below (Fig. 2).

Fig. 1. Simplified depiction of HPO axis and feedback mechanisms during 3.3. Conversion of cholesterol to pregnenolone
normal menstrual cycle and potential target tissues in normal menstrual
cycle and during administration of COCs. P, progesterone. Cholesterol in the ovary can arise by de novo synthesis
from acetate, plasma low-density lipoprotein cholesterol
(LDL-C) or intracellular stores of cholesterol [34]. The rate-
steroidogenesis, it appears that early development of the
limiting step is the transfer of cholesterol from the cytosol to
follicles is independent of FSH [26–29]. As the dominant
the mitochondria, a process that is regulated by the
follicle continues to grow, increasing amounts of E2 are
steroidogenic acute regulatory (STAR) protein [39–41].
secreted. The rising levels of E2 secreted into the circulation
Cholesterol in the mitochondria is converted to pregneno-
have a negative feedback effect on the HPO axis resulting in
lone, a C21 steroid that is the major precursor of all steroid
a decrease in FSH levels. However, between days 12 and 13,
hormones [36]. This step is catalyzed by the inner
the amount of E2 reaching the pituitary gland attains a critical
mitochondrial membrane cytochrome P450 side-chain
peak level. This dramatic increase in E2 results in a positive
cleavage enzyme (CYP11A1) and is regulated by LH and
feedback signal to the pituitary, triggering an increased
FSH in the theca and granulosa cells. It is mediated further
secretion of LH and, to a lesser extent, FSH — the midcycle
by cyclic adenosine monophosphate, STAR and steroido-
surge. The LH surge induces ovulation which occurs 24 to
genic factor 1 [40–42].
36 h after the LH peak [30–33]. E2 reaches peak values a
day before the LH surge in most normal menstrual cycles 3.4. Conversion of pregnenolone to progesterone
[30–33]. Coincidental with the surge of gonadotropins, there
is a precipitous drop in the secretion of estrogens by the Pregnenolone formed in the mitochondria is converted in
ovary that appears to precede ovulation [30–33] and occurs the cytoplasm to progesterone by the enzyme 3β-hydro-
34 to 36 h after the initiation of the LH surge. xysteroid dehydrogenase Δ 5,4 isomerase type 2 (HSD3B2)
Following ovulation, the granulosa and theca cells in the [43]. This microsomal enzyme both catalyzes the conversion
follicle that released the ovum, along with the surrounding of the carbon 3-hydroxyl group of pregnenolone to a keto
stroma, capillaries and connective tissue, undergo morpho- group and isomerizes the Δ 5 to Δ 4 double bond, giving rise
logical changes and evolve into the corpus luteum. This to progesterone.
process is referred to as luteinization. Both the granulosa and 3.5. Conversion of progesterone to androstenedione
theca cells are luteinized and begin secretion as a temporary and testosterone
endocrine gland. During the midluteal phase, the corpus
luteum secretes large amounts of progesterone and lesser Progesterone is then transformed to androstenedione by
amounts of E2 [34]. The functional life span of the corpus the microsomal P450c17 (CYP17A1), an enzyme that has
luteum is normally 14 days, after which it regresses unless both 17α-hydroxylase and the C17,20-lyase activities. In this
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727 709

HO
Cholesterol (LDL-Cholesterol)

Side Chain Cleavage

Enzyme (CYP11A1) StAR
CH3 CH3
C=O C=O

3β-Hydroxysteroid Dehydrogenase
∆5,4 Isomerase
(HSD3B2)
HO O
Pregnenolone Progesterone
17α -Hydroxylase 17α -Hydroxylase
(CYP17A1) (CYP17A1)
CH3 CH3
C=O C=O
OH OH
3β-Hydroxysteroid Dehydrogenase
∆5,4 Isomerase
(HSD3B2)

HO O
17α-Hydroxypregnenolone 17α-Hydroxyprogesterone

17,20-Lyase 17,20-Lyase
(CYP17A1) (CYP17A1)

O O

3β-Hydroxysteroid Dehydrogenase OH
5,4
∆ Isomerase
(HSD3B2) 17β-HSD
HO O
Dehydroepiandrosterone Androstenedione
O
Aromatase Testosterone
(CYP19A1)
O
Aromatase
(CYP19A1) O

17β-HSD

HO
Estrone HO
17β-Estradiol

Fig. 2. Biosynthesis of steroids from cholesterol in the normal ovary. The steroidogenic genes involved are shown in parentheses; 17β-HSD enzymes are
involved in the interconversion of androstenedione to testosterone and estrone to estradiol, respectively.

conversion, progesterone is first transformed to 17α-
hydroxyprogesterone followed by the cleavage of the C17–
C20 side chain to yield the C19 steroid androstenedione.
Alternatively, pregnenolone can be first converted to 17α-
hydroxypregnenolone and to dehydroepiandrosterone
(DHEA) by P450c17, and then DHEA is converted to
androstenedione by HSD3B2. Androstenedione is converted
to testosterone via the enzyme 17β-HSD. Testosterone can
also be formed by another pathway in which DHEA is first
converted to 5-androstene-3β,17β-diol by 17β-HSD, and
710 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
the latter compound is then converted to testosterone by
HSD3B2. During the follicular phase, this process is
regulated by a synergistic action of LH and FSH and by
paracrine interactions between the granulosa and theca cells,
a process that will be discussed later.
3.6. Conversion of androgens to estrogens
E1 and E2 are produced from androstenedione and
testosterone, respectively, by a complex series of enzymatic
reactions catalyzed by a single microsomal P450aro
(CYP19A1) enzyme, resulting in aromatization of ring A
of the androgen [44,45]. These estrogens are interconvert-
ible. E1 is converted to E2 and E2 to E1 through the action of
HSD17B1 and HSD17B2, respectively.
3.7. The two-cell hypothesis
Theca cells in the ovarian follicle produce and secrete the
androgens that diffuse into the granulosa cells where they are
aromatized to estrogens [44,46]. The hypothesis termed
the two-cell hypothesis of steroidogenesis proposes that the
theca and granulosa cells play synergistic roles in the
biosynthesis of E2 by the maturing preovulatory follicle.
During the follicular phase, LH acting via its receptors in the
theca cells stimulates the production of androstenedione and
testosterone from cholesterol, which then diffuse into the
granulosa cells where FSH stimulates the aromatization of
androstenedione and testosterone to E1 and E2, respectively.
Granulosa cells lack the ability to produce cholesterol,
pregnenolone or progesterone and depend on the obligatory
estrogen precursor androstenedione produced in the theca
cells. The corpus luteum formed after ovulation accumulates
large deposits of cholesterol derived primarily from LDL-C.
The theca and granulosa cells, under the influence of
gonadotropins, are transformed into theca lutein and
granulosa lutein cells, respectively. These luteinized cells
are now the major source of sex steroids secreted by the
ovary postovulation.
It is important to note that the conversions of androstene-
dione to testosterone and E1 to E2 are both reversible, and in
the ovary during both phases of the menstrual cycle, the
predominant estrogen secreted is E2. Although, in ovulatory
women, this is the main mechanism for the formation of E2,
small amounts of E2 are formed in extraglandular tissues
Table 1
Plasma concentrations, ovarian secretion rates and total production rates of estradiol, E1 and progesterone during the various phases of the menstrual cycle
Steroid Early follicular Late follicular
Plasma Secretion rate Production rate Plasma
concentration (mg/day) (mg/day) concentration (mg/day)
(pg/mL) (pg/mL)
Estradiol 60 0.07 0.08 330–700
E1 50 0.08 0.11 150–300
Progesterone
Modified from Little and Billiar [30], MacDonald et al. [31], Baird et al. [32], Baird and Guevara [33].
such as the breast, skin, adipose, brain, bone and muscles
from circulating DHEA, mainly of adrenal origin [47–53].
E1 can also be metabolized to E2 in extraglandular sites.
However, only about 5% of E2 formed by this extraglandular
pathway enters the circulation [54–57].
Based on the pathways just discussed, the plasma
concentration, ovarian secretion rate and production rate
(sum of rates of extraglandular and ovarian secretions) of E2,
E1 and progesterone during the menstrual cycle are shown in
Table 1. E2 and E1 secretion and plasma concentrations
are lowest during the early follicular phase, highest during
the late follicular phase and substantial during the luteal
phase [30–33].
3.8. In vivo transport of estrogen and progesterone
Serum E2 and progesterone reversibly bind to sex
hormone-binding globulin (SHBG) and corticosteroid-bind-
ing globulin (CBG), respectively. This form of binding of
steroid hormones plays an important role in the transport and
distribution of these hormones. Circulating E2 and proges-
terone are primarily bound nonspecifically to serum albumin
with low affinity and specifically with high affinity to SHBG
and CBG [58–60]. Only a small fraction (1%–3%) of these
hormones circulate in the unbound or free form [59,60]. It is
generally recognized that only the free (unbound) form of
steroid hormones is able to enter the target cells to exert its
biological effect, or be further metabolized and excreted.
There is, however, some suggestive evidence that some
protein-bound steroids also can enter the cell, but the
physiological significance of this observation remains to be
established [61]. Since steroid hormones bind to serum
albumin with low affinity (1×10 4–1×10 6 Ka) and high
capacity, these bound hormones can dissociate to free
hormones readily, and the pool of albumin-bound hormone
is also considered to be available for biological action. It has
been estimated that, in women with normal menstrual cycles,
approximately 60% of the E2 in the circulation is bound to
albumin, and 38% is bound to SHBG (Ka= 1×10 8–1×10 9)
[62,63]. In contrast, only about 17% of progesterone is
bound to CBG; the remainder is bound predominantly to
albumin [60].
The levels of SHBG synthesized in the liver are controlled
by the levels of various hormones. Thus, testosterone and
Midluteal
Secretion rate Production rate Plasma Secretion rate Production
(mg/day) concentration (mg/day) rate (mg/day)
(pg/mL)
0.4–0.8 0.44–0.94 200 0.25 0.27
0.25–0.5 0.33–0.66 110 0.16 0.24
11,300 24 25
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
insulin inhibit SHBG synthesis, while E2 and thyroxine
stimulate SHBG formation [64]. The oral administration
of E2 increases SHBG levels, resulting in a greater
percentage of E2 bound to SHBG, and therefore, a lesser
amount of free hormone will be available for biological
action. In contrast, androgen excess, hypothyroidism and
obesity lower SHBG levels and result in an increase in the
free fraction of E2 [65]. The extent and degree of binding of
E2 to serum proteins not only determines the amount of E2
available for biological action but, more importantly, can
have an effect on the overall metabolic clearance rate and
other pharmacokinetic parameters [38,66], which will be
addressed in subsequent sections.
3.9. Metabolism of endogenous estradiol
Besides the reversible metabolic interconversions be-
tween E1 and E2, estrogens undergo irreversible metabolism
in tissues such as the liver and the kidney and, to some
extent, in target tissues such as the endometrium and brain
[38]. The major irreversible metabolic transformations of
estrogens occur in the A and D rings, giving rise to mainly
2-, 4- and 16α-hydroxylated metabolites (Fig. 3).
The 2- and 4-hydroxylated metabolites are the so-called
catechol estrogens. In vivo and in vitro data indicate that
these metabolites are formed in humans, and, more
importantly, it has been suggested that the oncogenic
potential of E1 and E2 depends on the extent of their
metabolism to extremely labile catechol estrogens. The
hypothesis, in general, is that the cytochrome P450-
dependent oxidative metabolism of estrogens leads to
the formation of metabolites that generate reactive free
radicals that can cause oxidative stress and genomic damage
2 and 4-Hydroxy-Catechol Estrogens
O HO
HO
Estrone
HO
-Hydroxyestrone
Fig. 3. In vivo and in vitro metabolism of estrone via catechol estrogens and 16α-hydroxylation. The potential for adduct formation with macromolecules is
indicated. The α-ketol is circled. Modified from Bhavnani [66].
711
leading to carcinogenesis. Although the mechanisms have
not been delineated, it appears that these hydroxylated
metabolites are easily auto-oxidized to semiquinones
and quinones that can covalently bind to DNA, thereby
resulting in DNA damage [67–72]. To date, there is no direct
evidence that 2- and 4-hydroxyestrogens are carcinogenic in
vivo in humans. Various proposed hypotheses and mecha-
nisms are circumstantial.
Apart from the metabolism of E1 and E2 to catechol
estrogens, these estrogens also can undergo 16α-hydroxyl-
ation (P450 3A4) to form estriol, which is rapidly cleared
and excreted in urine as estriol glucuronide. In addition to
estriol (16α-hydroxyestradiol), 16α-hydroxyestrone also is
formed, and this 16α-hydroxylated estrogen has been
implicated in the oncogenic process [73,74]. The hypothesis
is based on the demonstration that 16α-hydroxyestrone, a
major urinary metabolite of E2 and E1, can form large stable
covalent adducts (compounds) with macromolecules such as
DNA and proteins (Fig. 3) [75,76]. It has further been
suggested that this adduct formation plays a role in the
etiology of breast cancer [75,76]. Based on in vitro
experiments, it has been proposed that the covalent adduct
formation between 16α-hydroxyestrone and macromole-
cules occurs because of the presence of D ring α-ketol
(Fig. 3, circled). It also has been hypothesized that estrogen
metabolism favoring 16α-hydroxylation leads to increased
cancer risk in postmenopausal women [77]. Based on the
observation that 16α-hydroxyestrone is a potent estrogen
whereas 2-hydroxyestrone is relatively inactive, it has been
proposed that the ratio of urinary 2-hydroxyestrone to 16α-
hydroxyestrone is a predictor of cancer risk and that this ratio
is inversely correlated with the risk for breast and cervical
cancers [77,78]. In contrast, a number of well-carried-out
OH
Estradiol
Potential Stable Adducts
O
OH
712 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
studies did not find a significant correlation between the ratio
of urinary 2-hydroxyestrone and 16α-hydroxyestrone and
breast cancer risk in both premenopausal and postmeno-
pausal women, with or without breast cancer [79–82].
The circulating levels of catechol and 16α-hydroxylated
estrogens obtained after oral administration of the new
E2-based COCs need to be determined. However, one would
expect them to be relatively low owing to their extremely
high MCRs.
4. Pharmacokinetics of E2 and EE
4.1. Pharmacokinetics of E2
4.1.1. Absorption and distribution
E2 is rapidly absorbed following oral administration of
therapeutic doses [83]. Circulating E2 levels are dose
dependent. After a single oral dose administration of 2 mg
E2 to young women, maximum plasma E2 levels of 30 to
50 pg/mL were observed within 6 to 10 h [84]. The levels
increased linearly up to an E2 dose of 4 mg, but absorption
was incomplete after a dose of 8 mg.
Although reduced particle size (micronization) of orally
administered E2 has been shown to improve its absorption
[85], E2 still has a very low bioavailability. Together with the
first-pass metabolism in the liver, about 95% of the
administered E2 is metabolized before entering the systemic
circulation [86]; less than 5% of the administered E2 is
bioavailable. It has been shown that, of the administered E2
dose, 15% is absorbed as E1, 25% as E1 sulfate (E1S), 25% as
E1 glucuronide and 25% as estradiol glucuronide.
As shown earlier in premenopausal women, approxi-
mately 38% and 60% of circulating E2 are bound to SHBG
and albumin, respectively, so that about 2% of E2 is in free
form [59]. However, during oral E2 treatment, serum SHBG
levels increase, resulting in a reduced free E2 fraction.
4.1.2. Metabolism
When E2 is administered orally, it undergoes extensive
hepatic first-pass metabolism. A considerable part of the
administered dose is metabolized in the gastrointestinal
mucosa, predominantly through the action of HSD17B2,
forming E1. Following its absorption, partly metabolized
and unmetabolized E2 enters the portal vein blood, which
perfuses the liver where a variety of enzymes, including
hydroxylases, methyltransferases, and sulfuryl and glu-
curonyl transferases, transform E2 and E1 to a variety
of metabolites.
Estrogens are excreted to a significant extent in bile and
are partly reabsorbed from the intestine. The enterohepatic
recirculation of E2 and E1 has a delaying effect on their final
elimination from the body [87,88]. Because of the large pool
of estrogen metabolites formed and the enterohepatic
recirculation, the terminal half-life of E2 represents a
composite parameter that is dependent on these processes
and is in the range of about 13 to 20 h [89].
As described earlier, E2 and E1 are metabolized to
numerous metabolites. The metabolites that contain a
hydroxyl group can be conjugated via sulfuryl or glucuronyl
transferases to form a variety of hydroxylated and nonhy-
droxylated sulfates and glucuronides of E2 and E1. If we take
into account all the unconjugated and conjugated forms,
there are over 100 metabolites of E2 and E1 found in the
circulation. The estrogen metabolites formed from exoge-
nous E2 are essentially the same as those formed from
endogenous E2 and E1 except that they are present in much
higher concentrations.
E1S is the principal circulating metabolite of E 2,
irrespective of the route of administration. About 15% of
orally administered E2 is converted to E1 and about 65% to
E1S [90]. E1S appears to form a pool from which E2 can be
regenerated, first by transformation of E1S to E1 through the
action of sulfatase and then conversion of E1 to E2 via the
action of HSD17B1. About 5% of E1 and 1.4% of E1S can be
converted back to E2. Another 21% of E1S can be
transformed to E1, and the conversion of E1 to E1S is
about 54%.
Because of the presence of the highly active 17β-HSD in
the gastrointestinal mucosa, serum levels of E1 are several-
fold higher than those of E2. Following oral administration of
1 mg micronized E2 to a postmenopausal woman, serum E2
levels are in the range of 30 to 50 pg/mL, whereas the
corresponding range of E1 levels is 150 to 300 pg/mL [91].
The E1 levels are, on average, about five times higher than
those of E2 and can be about 10 times higher in some
women. The E1/E2 ratio obtained after oral E2 administration
differs from the corresponding ratios found in premenopau-
sal women during the menstrual cycle and in postmeno-
pausal women not receiving oral estrogen therapy; these
ratios are, on average, 0.6:1 and 3:1, respectively. The
biologic significance of the different E1/E2 ratios is not
known. In contrast to the oral route of E2 administration, the
E1/E2 ratio is approximately 1 when E2 is administered
parenterally (e.g., by transdermal patch).
When E2 is administered orally, serum levels of E1S rise
dramatically. The biologic significance of the elevated E1S
levels obtained after oral E2 administration is not known;
however, E1S itself has no biologic activity. When the E2
derivative E2V is administered orally, it is rapidly and
completely hydrolyzed to E2 during the hepatic first pass
[92]; however, there may be considerable intersubject
variability in the E2 concentration obtained. The metabolism
and pharmacokinetics of E2 derived from E2V are the same
as those of E2.
4.1.3. Excretion
Following oral administration of 2 mg of E2V to
premenopausal women, 54% of the dose was recovered in
urine and only 6% in the feces [93], even though a
substantial amount of E2 has been shown to be excreted in
bile [94]. Thus, it appears that there is a highly efficient
enterohepatic recirculation of biliary excreted estrogen
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
metabolites which, following reabsorption, are metabolized
further and eventually excreted in urine [89]. After oral
administration of 3H-E2, the urinary estrogen metabolites are
predominantly in the form of glucuronides, but a substantial
amount of sulfated estrogen is also present [86]. The main
urinary estrogens include glucuronides of E1 (13%–30%),
2-hydroxy-E1 (2.6%–10.1%), E2 (5.2%–7.5%), E3 (2.0%-
5.9%) and 16α-hydroxy-E1 (1.0%–2.9%).
4.2. Pharmacokinetics of ethinyl estradiol
4.2.1. Absorption and distribution
Similar to the absorption of E2, EE is rapidly and
completely absorbed following oral administration of thera-
peutic doses [95]. After the administration of 30 mcg EE, peak
plasma EE levels of 90 to 130 pg/mL are found within 1 to 2 h
after ingestion [95]. Occasionally, a secondary peak can be
observed about 10 to 14 h following oral EE administration,
which is attributed to the enterohepatic circulation of EE.
Dose proportionality in EE levels is observed with EE doses
of 20 to 100 mcg [95]. Although there is considerable
presystemic metabolism during the hepatic first pass of orally
administered EE, it is not as extensive as that of E2. The mean
oral bioavailability of EE is approximately 45%, with a large
inter- and intraindividual variability in the range of 20% to
65% [96]. Owing to the large variability in EE bioavailability,
EE levels produced by 35 mcg EE in one woman may be
indistinguishable from those generated by 50 mcg in another
woman [97].
Unlike E2, which binds with high affinity to SHBG in
blood, EE does not bind to SHBG [98]. Following oral
administration of EE, the time course of plasma EE levels
can be described by a two-compartment model in most cases:
a rapid distribution phase followed by a terminal disposition
phase that is characterized by a half-life in the range of
approximately 5 to 30 h [96]. The large range in terminal
half-life can be attributed only partly to interpatient
variability. The other important contributing factor pertains
to measurement of low levels of EE [89]. When EE is
administered in doses b 50 mcg, plasma EE levels at 24 h are
usually at the lower limit of measurement of the EE assays.
Therefore, a terminal half-life that is longer than 10 h cannot
be determined with any accuracy; this is a limitation of most
published half-life data of EE. More sensitive EE assays
have to be developed to obtain accurate EE terminal half-
lives (e.g., by use of mass spectrometry assays).
During repeated oral administration of EE, an increase in
trough serum EE levels can be observed until approximately
5 to 10 days after initiating treatment, with only minimal
change until the end of the treatment cycle [99,100]. Several
studies have demonstrated an increase in serum EE levels
between 30% and 60% within a treatment cycle with
different COCs [89]. This large range can be explained by
the pharmacokinetic accumulation of EE and is determined
by calculating the ratio of the terminal half-life of EE and the
dosing interval. Accumulation factors ranging from 1.23 to
713
1.77 have been calculated for EE, with a terminal half-life of
10 to 20 h and a 24-h dosing interval [89]. This means that, in
comparison to single-dose EE administration, one can expect
an accumulation between 23% and 77% during repeated oral
EE administration.
4.2.2. Metabolism
Oxidation reactions at various carbons of the steroid
nucleus play a major role in the metabolism of EE, similar to
that of E2. Quantitatively, the most important pathways of
E2 metabolism involve 2-hydroxylation and 16α-hydroxyl-
ation, as discussed earlier. In contrast, 16α-hydroxylation
of EE has not been reported presumably owing to blockage
(steric hindrance) by the ethinyl group at carbon 17. The
2-hydroxylation of EE is quantitatively the most important
pathway of EE metabolism [89]. Hydroxylations of EE
at carbons 4, 6 and 16β have been reported but appear
to contribute only to a small extent to its metabolism.
Whether the absence of 16α-hydroxylation of EE compared
with E2 is of any pharmacological significance remains to
be determined.
A considerable part of the intersubject variability in EE
pharmacokinetics, which will be discussed later, can be
attributed to differences in extent of 2-hydroxylation of EE,
which is primarily catalyzed by hepatic cytochrome P450
3A4. A wide variation in levels of this enzyme has been
demonstrated among individuals [101].
Both EE and its hydroxylated metabolites undergo
extensive conjugation, primarily in the liver. EE is rapidly
conjugated partly to a glucuronide (EE-3-glucuronide and
EE-17-glucuronide), which is inactive and undergoes rapid
renal clearance, and to EE-3-sulfate and EE-17-sulfate,
which circulate at concentrations that are about 10-fold
higher than EE itself [102]. During enterohepatic recircula-
tion, the EE sulfates are partially deconjugated to EE (the
17-sulfate to about 12% and the 3-sulfate to about 20%), thus
providing a relatively small contribution to the circulating
unconjugated EE.
4.2.3. Excretion
In contrast to oral administration of E2, considerably more
of the total excreted EE is eliminated in feces compared with
urine. In one study [103], approximately 62% of the total
excreted radioactive EE and its metabolites were eliminated
in feces and about 38% in urine following oral administration
of 3H-EE to women.
About 6% of the administered oral EE dose appears as
untransformed EE in urine [104], and the remaining portion
includes predominantly conjugated EE metabolites, which
are mostly (about 80%) in the form of glucuronides (3-
glucuronides; 17-glucuronides; 3,17-diglucuronides); sulfat-
ed forms constitute only about 8% to 10% [89]. About 9% of
orally administered EE appears as untransformed EE in
feces, whereas the conjugated forms are poorly characterized
[89]. However, the predominant forms are EE glucuronide
and EE sulfate in bile [105].
714 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
5. Mechanism of action of EE and E2
Estrogens interact with estrogen receptors (ERs) that are
members of a superfamily of nuclear receptors. Estrogen
receptor α (ERα) and estrogen receptor β (ERβ) can be
detected in a broad spectrum of tissues. Both receptor types
are expressed at similar levels in some organs, whereas one
subtype predominates in other organs. In addition, both
receptor subtypes may be present in the same tissue but in
different cell types. ERα is mainly expressed in the uterus,
prostate, ovary, testes, epididymis, bone, breast, various
regions of the brain, white adipose tissue and liver, whereas
ERβ is expressed primarily in the colon, prostate, testis,
ovary, bone marrow, salivary gland, vascular endothelium
and certain regions of the brain [106]. Both E2 and EE exert
their biological effects via interactions with estrogen
receptors by the same mechanism that has been extensively
reviewed [107–111] and will not be discussed here.
Based on this mechanism, it has been shown that E2 is
100-fold less active compared with EE, and it has been
recognized for decades that much higher doses of oral E2 are
required to bring about the same degree of biological effect
as by EE [112].
6. Pharmacodynamic effects of E2 and EE
Pharmacodynamic effects of orally administered E2 have
been studied primarily in postmenopausal women, whereas
pharmacodynamic effects of oral EE have mostly been
studied in combination with a progestin in premenopausal
women. We provide a general overview of the pharmaco-
dynamic effects of COCs containing either EE or E2 in
women in the following sections.
6.1. Metabolic effects
6.1.1. Lipids
It has been known for over 30 years that the comparison
of earlier high-dose COCs with more recent lower-dose
formulations shows that the effect of COCs on the levels of
lipoproteins depends on the ratio of estrogen and progestin in
each formulation [113]. Premenopausal women who used
COCs with a high-dose estrogen/low-dose progestin ratio
were found to have significantly higher concentrations of
high-density lipoprotein cholesterol (HDL-C) compared
with nonusers [114]. In contrast, women who used low-
estrogen/high-progestin COCs had a significantly lower
level of HDL-C but higher levels of LDL-C. Whether these
effects on lipoprotein cholesterol levels affect cardiovascular
risk is controversial. Some of the metabolic changes such as
increased LDL-C, triglycerides and insulin levels and
decreased levels of HDL-C are similar to those observed in
individuals who are at increased risk of coronary heart
disease (CHD) [114]. These findings have been reviewed
previously [115]. Interestingly, not only does the type of
progestin play a role, but the type of regimen also seems to
determine the effect on levels of unfavorable lipoproteins.
Several short-term clinical studies using various newer
COC formulations consisting of EE b 50 mcg combined with
one of a variety of progestins such as levonorgestrel (LNG),
norethindrone, norgestimate, gestodene or desogestrel gen-
erally show an increase in triglycerides, which is most likely
ascribed to the estrogen component. Variable effects on
LDL-C, HDL-C, apolipoprotein A and apolipoprotein B also
were found. The changes were small and appeared to have no
significant impact on lipid profiles after 12 months of use in
most of the studies [116–122].
Some of these short-term studies suggested small
differences between monophasic and triphasic formulations.
It is highly unlikely that subtle changes in lipid profiles can
have a significant impact on the incidence of cardiovascular
disease in young women using the newer lower-dose COCs.
This is in keeping with the rarity of arterial disease diagnosed
in young women [123] and, more importantly, observations
that 64% of young women who had sustained a myocardial
infarction (MI) while they were using COCs did not show
angiographic atherosclerosis [124]. Similarly, a review of 14
reports of MI and use of COCs showed no evidence of
significant fixed obstruction by arteriography in these
women [125]. The authors [124] concluded that MIs in
COCs users may be a discrete disease entity unrelated to
coronary atherosclerosis. A large study by the Royal College
of General Practitioners (RCGP) also found no significant
effect of COC use on acute MI in nonsmokers; however, the
risk was significantly higher in smokers who were over the
age of 35 years [126].
A review of numerous studies dating from 1980 to 1993
including those involving the newer progestins (gestodene,
norgestimate or desogestrel) combined with 35 or b 35 mcg
of EE indicated that these newer progestins were less
androgenic than the older formulations, specifically those
containing LNG and norethindrone. The new generation of
progestins has a lower impact on apolipoprotein and
carbohydrate metabolism; however, whether these small
differences have any clinical relevance remains to be
established [127]. In a more recent case–control study, a
direct comparison of users of more recent formulations of
COCs versus older formulations showed that use of newer-
generation COCs was not associated with an excess risk for
MI [odds ratio (OR), 0.28; confidence interval (CI), 0.09–
0.86] [128]. The study further showed that the risk was
ameliorated in smokers who used the newer COCs. A
number of studies have shown that smoking is the most
important independent risk factor and that concomitant use
of COCs by smokers who were over the age of 35 years
significantly increased the risk of MI [126,129,130]. These
observations and a number of others were considered by a
consensus panel [131], and their recommendations were that
patients over 35 years of age who smoked heavily (N 15
cigarettes/day) should be “denied the use of oral contracep-
tives.” Their review of COCs containing 20 mcg EE
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
suggested that this dose may be a safer alternative, even for
those who are over 35 years of age and smoke occasionally.
However, the general consensus is that, in women over 35
years of age who are heavy smokers, COCs are most
definitely contraindicated, as recommended by the US
Centers for Disease Control and Prevention [132]. The
results from another large population-based case–control
study (3989 patients and 4900 controls) similarly showed
that both current and former smokers had a moderately
increased risk of venous thromboembolism (VTE) (OR,
1.43; CI, 1.28–1.60 in current smokers and OR, 1.23; CI,
1.09–1.38 in former smokers) compared with nonsmokers
[133]. More importantly, women who were current smokers
and used COCs had an approximately ninefold higher risk of
VTE (OR, 8.79; CI, 5.73–13.49) than nonsmokers who were
not COC users. The risk was fivefold higher in women who
were identified as having a factor V Leiden mutation and
current smokers, and for those identified with the prothrom-
bin 20210 A mutation, the risk was sixfold higher compared
to women without the mutation [133].
The effects of an E2-based COC on lipids, carbohydrates
and hemostasis were compared to an EE-based COC in a
recent study [134]. A total of 121 women, aged 18–50 years,
were randomly assigned to receive E2 (1.5 mg)/NOMAC
(2.5 mg) in a 24/4-day regimen (N= 60) or EE (30 mcg)/LNG
(150 mcg) in a 21/7-day regimen (N= 61) for six cycles. The
E2/NOMAC group showed a favorable lipid profile
compared to the EE/LNG group; however, the changes
were overall small and within the normal range, and may be
due to the differences in the regimen (24 vs. 21 days) and/or
the progestins in the formulations. Detailed long-
term clinical studies are needed to evaluate the effects of
E2-based COCs on lipid parameters in comparison to EE-
based COCs.
Because of the rare finding of CHD in young women, the
determination of the safety profile of new COC formulations
is an ongoing challenge. Whether the subtle minimal
changes in metabolic parameters among different COCs
have any relevant clinical significance has not yet been
demonstrated. The sample size in studies required to firmly
evaluate these associations would be extremely large so as to
make such studies difficult to investigate [123].
6.2. Carbohydrates
Older high-dose COCs were associated with changes in
carbohydrate metabolism in women. Elevated blood sugar
and insulin levels along with impaired glucose tolerance
were observed in high-dose COC users [135–137]. Since
these effects were thought to be mainly due to the estrogen
component of COC preparations, the estrogen dose has
significantly declined over the past 25 years.
Another study [115] explored the effects of nine different
oral contraceptive formulations on lipid and carbohydrate
metabolism; seven COCs with various doses and types of
progestins combined with 30 mcg to 40 mcg EE, in addition
715
to two progestin-only formulations, were compared to non-
COC use. Depending on the type of progestin and its dose in
the COC users, the plasma glucose levels obtained following
a glucose tolerance test were 43% to 61% higher than in
controls, insulin response was 12% to 40% higher, and the
C-peptide response was 18% to 45% higher than in nonusers.
The progestin-only formulations were associated with only
minor metabolic effects compared with nonusers. Thus, it
would appear that insulin sensitivity is mainly affected by the
estrogenic component, and the magnitude of the response
can be modified by the dose and type of progestin [115].
The association between COC use and incidence of type 2
diabetes [non-insulin-dependent diabetes mellitus
(NIDDM)] was examined in a large prospective study (the
Nurses' Health Study cohort) [138]. The findings indicate
that current users of COCs did not have an increased risk of
NIDDM [relative risk (RR), 0.86; 95% CI, 0.45–1.61]
compared with never users. In this study, 98,590 nurses,
aged 25 to 42 years and free of diabetes, coronary heart
disease, stroke and cancer, were followed for 4 years. No
significant increase was detected in NIDDM among current
users or past users of low-dose COC preparations. The
authors also concluded in this study that the number of cases
of NIDDM in COC users was very small (185 cases) during
352,067 person-years of follow-up, indicating a low absolute
risk of this disease in young women [138].
A large epidemiologic study [139] surveyed data from 89
randomly selected locations in the United States. The study
findings showed that the vast majority of current COC users
were using newer low-dose estrogen monophasic and
triphasic formulations. Moreover, the study found that
current COC users did not have adverse carbohydrate-
related side effects such as elevated levels of hemoglobin
A1c, fasting glucose, insulin and C-peptide levels. Similarly,
in former users of low-dose COCs, there were no significant
changes in these parameters. Thus, low-dose EE-based
COCs are not associated with any adverse changes in
glucose metabolism. Studies that investigated the effect of
E2-based COCs on carbohydrate metabolism in healthy
young premenopausal women are scarce. The short-term
study by Ågren et al. [134] described above showed minor
changes in carbohydrate metabolism between E2- and EE-
based COCs. Increases in glucose and insulin were
significantly greater with the latter formulation. This
finding is similar to that reported in other studies, but it is
unknown whether these observations have any clinical
significance [140,141].
6.3. Vasculature
Vascular endothelial and smooth muscle cells express
both ERα and ERβ. Estrogen has both rapid vasodilatory
effects and longer-term actions that inhibit the response to
vascular injury and prevent atherosclerosis [142]. Some of
the rapid estrogen signaling in the vasculature may be
mediated through the activation of G-protein-coupled
716 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
estrogen receptors [143]. Estrogen promotes vasodilation by
inducing the production of endothelial nitric oxide (NO)
synthase and NO release. NO has strong vasodilatory and
antithrombotic properties and triggers the formation of cyclic
guanosine monophosphate (cGMP). Estrogen also affects
the production of other endothelial factors, including
products of arachidonic acid, by increasing the activity of
cyclooxygenase and prostacyclin synthase [142].
In postmenopausal women, short- and long-term E2
dosing enhances flow-mediated dilation (reactive hyper-
emia) [144,145]. However, no studies have explored
the effect of EE without concomitant progestin administra-
tion on vascular blood flow in women. In premenopausal
women, basal NO production and release (measured by
changes in flow-mediated dilation) appeared to be enhanced
by use of COCs containing EE [146]. EE-containing COCs
also influenced the renal excretion of various vasoactive
markers: cGMP excretion was significantly enhanced and
thromboxane metabolite excretion was decreased after 12
cycles [147].
6.4. Hypertension
Blood pressure (BP) varies during the menstrual cycle
[148]. A number of studies have shown that use of high-dose
COCs, containing at least 50 mcg EE and 1 mg to 4 mg of
progestin, is associated with a moderate increase in BP in
approximately 5% of women [149]. Some studies have
assessed the rise in BP according to the estrogen dose and
progestin type used in the formulation. Thus, use of 250 mcg
LNG+50 mcg EE and 1 mg norethisterone (NET)+30 mcg
EE for up to a year was not associated with a significant BP
increase. In contrast, use of 250 mcg LNG+30 mcg EE
showed a slight but significant increase [150]. It would
therefore appear that the effect of the progestin to estrogen
ratio in COCs may be more important than just the dose on
BP changes. Another study that compared four COCs
containing 1 mg NET, 150 mcg LNG, 150 mcg desogestrel
or 75 mcg gestodene combined with 30 mcg EE showed that
all four formulations were associated with a small but
significant increase in BP. No woman in the trial developed
clinically significant hypertension necessitating discontinu-
ation of the COC [151].
A large prospective cohort study [149] consisting of
68,297 female nurses aged 25 to 42 years found that,
compared with women who had never used COCs, the age-
adjusted RR for hypertension was 1.5 (95% CI, 1.2–1.8) for
current users and 1.1 (95% CI, 0.9–1.2) for past users. The
calculated incidence of hypertension was only 41.5 cases per
10,000 women per year. This risk decreased soon after
cessation of COC use, and past users had only a slightly
increased risk.
6.5. Hemostasis
The coagulation and fibrinolytic systems are two separate
but interlinked cascades of proteins that regulate the
production and breakdown of fibrin. The purpose of the
clotting mechanism is to produce thrombin (activated factor
II), which converts fibrinogen to a fibrin clot. Thrombin is
generated from prothrombin through the action of factor X in
the presence of factor V and factor VIII. The coagulation
pathway is initiated by the release of the inhibitor, tissue
factor, which activates factor VII; the latter factor, in turn,
activates factor X. In addition to tissue factor, other
inhibitors that safeguard against excessive thrombosis
include antithrombin III, which inhibits the formation of
thrombin, and protein C and protein S, which inhibit the
formation of factors V and VIII.
The coagulation system is balanced by the fibrinolytic
system, which involves the degradation of fibrin and the
lysing of clots by plasmin. Plasmin is formed from
plasminogen through the action of tissue-type plasminogen
(t-PA), which is balanced by a specific inhibitor, plasmin-
ogen activator inhibitor type 1 (PAI-1).
A variety of laboratory assays are used to assess
coagulatory and fibrinolytic activity. Prothrombin fragment
1+2 (F1+2) and the thrombin/antithrombin complex are
determined to evaluate the thrombin generation rate. Tissue
factor antigen, factor VII activity and F1+2 reflect
coagulatory activity. Antithrombin III, protein C and protein
S are important measures of the inhibition of thrombin
generation and thrombin activity. Assays used to assess
fibrinolytic activity include the plasmin–antiplasmin com-
plex, t-PA and PAI-1. Finally, D-dimer, which is a
degradation product of fibrin, is used to assess the net
activity of the hemostatic system.
Studies investigating the effect of EE or E2 alone on the
coagulation and fibrinolytic systems in premenopausal
women are lacking. Existing studies involving the effects
of EE on these systems have been carried out with EE-based
COCs with different progestins. Since E2-based COCs are
relatively new, there is a paucity of data on their effects on
the hemostatic system. Some of these studies with EE- and
E2-based COCs will now be discussed.
It has been shown that both the estrogenic and
progestational components of COCs influence hemostasis.
High-dose COCs (50 mcg EE) increase the production of
clotting factors such as factor V, factor VIII, factor X and
fibrinogen [152]. Some studies have shown that monophasic
and multiphasic low-dose (30–35 mcg EE) COCs have no
significant clinical impact on the coagulation system and that
slight increases in thrombin formation are offset by increased
fibrinolytic activity [153,154]. However, other studies with
low-dose COCs show an increase in clotting factors
associated with an increase in platelet activity [155]. In a
study by the Oral Contraceptive and Hemostasis Study
Group [156], the effects of COCs on 24 hemostatic variables
were determined in 747 healthy nonsmoking women. The
women were treated for six cycles with one of seven
monophasic COCs containing 20, 30 or 50 mcg EE
combined with one of four different progestins. The results
show that the clotting factor responses were influenced not
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
only by the progestin component but also by the EE dose (30
vs. 50 mcg).
In the six-cycle study by Ågren et al. [134], which
compared E2 (1.5 mg)/NOMAC (2.5 mg) vs. EE (30 mcg)/
LNG (150 mcg), both formulations induced minimal
changes from baseline to the end of treatment in procoagu-
latory factors II (prothrombin), VIIa and VIII, whereas factor
VIIc was essentially unchanged in the E2/NOMAC group but
decreased significantly by 12.7% in the EE/LNG group.
Results of the anticoagulatory indices showed relatively
small changes from baseline in each group (E2/NOMAC vs.
EE/LNG), with significant differences in some but not other
indices that included the activated partial thromboplastin
time-based activated protein C (APC) sensitivity ratio (3.3%
vs. 2.0%; p=.97), antithrombin III (3.9% vs. − 3.6%, p=
.004), protein C (− 3.1% vs. 8.2%; p=.002), and free (13.3%
vs. 11.9%, p=.97) and total (4.7% vs. − 3.6%, pb.001)
protein S. A substantial change from baseline was observed
in the endogenous thrombin potential-based APC sensitivity
ratio (60% vs. 146%; p=.001). As for markers of thrombin
turnover, the percent change from baseline to end of
treatment showed an increase in F1+2 in the EE/LNG
group but not in the E2/NOMAC group (− 1.7% vs. 13.5%;
p=.085), but D-dimer was essentially unchanged in both
groups. However, the D-dimer results are inconclusive
because more than 50% of the values were below the
detection limit. A notable observation in the hemostatic data
is the large variability of virtually all the indices measured in
each of these two treatment groups. Also, although no
reference ranges were reported, it appears that most, if not
all, changes with treatment in the hemostatic parameter
measures remained within the normal range with both
contraceptive formulations.
In the same study, C-reactive protein (CRP), which is a
marker of cardiovascular risk, was also measured in both
treatment groups. The % change from baseline was greater in
the EE/LNG group compared to the E2/NOMAC group
(258% vs. 66.7%, respectively; p≤.001). However, the CRP
levels in the EE/LNG group are within the normal range of
CRP values for premenopausal women [134].
A study similar to the one just described compared the
hemostatic effects of E2/NOMAC with those of EE/LNG
using a lower dose of the EE/LNG formulation (20 mcg EE
combined with 100 mcg LNG) and a shorter treatment period
(three consecutive cycles instead of six cycles) [157]. The
results show that although some of the changes from baseline
to end of treatment in the measures of the coagulation and
fibrinolysis parameters differed between the two groups,
most of the changes were relatively small, and the end of
treatment values are within the normal range. Also, no
significant between-group differences were found on platelet
aggregation at the end of treatment.
In another related study [158], the hemostatic effects of a
multiphasic formulation consisting of E2V (1–3 mg)
combined with dienogest (2–3 mg) were compared with
those of a triphasic formulation containing EE (30–40 mcg)
717
combined with LNG (50–125 mcg) during a treatment
period of seven cycles. Changes in coagulation and
fibrinolytic parameter values from baseline to end of
treatment were relatively small and remained within the
range of normal values.
Studies have shown that COCs can induce activities of the
coagulation system, which are attributed to the estrogenic
component of the COC [159]. Activation of the coagulation
system is especially evident in COC users who smoke. COCs
containing a high dose of EE (50 mcg) induce greater
changes in coagulation than those containing 30 or 35 mcg
EE, which still induce a significant activation of coagulation
parameters [160]. In contrast, COCs with 20 mcg EE appear
to have a negligible or no effect on these parameters. In
nonsmoking COC users, any procoagulatory effects that may
occur are counterbalanced by fibrinolytic effects. However,
in smokers, compensating fibrinolytic effects to offset
procoagulatory effects observed with COCs containing 30
mcg EE are absent, thereby shifting the hemostatic profile
toward a hypercoagulable state.
Based on the limited data available from the short-term
studies that compared the effects of E2 with EE, each
combined with a different progestin, on hemostatic param-
eters, it appears that the effects of the E2- and EE-based
formulations are similar. Long-term studies on hemostatic
parameters using different types and doses of progestins
combined with different doses of E2 or EE are needed.
6.6. Bone
During puberty, endogenous estrogen helps to shape the
skeleton and leads to growth of the long bones and
epiphyseal closure [161]. The estrogens stimulate chondro-
genesis in the epiphyseal growth plate. Oral [162],
transdermal [163–165] and transvaginal [166] E2 increases
bone mineral density in postmenopausal women. Although
the mechanism of action of E2 on bone is not understood
fully, E2 may increase bone mass by decreasing the number
and activity of osteoclasts, thus minimizing bone resorption;
it also may replace lost bone mineral [167]. ERs are found in
osteoblasts (bone forming cells) and may indirectly control
bone resorption by osteoclasts [168].
Since EE and, more recently, E2 are administered in
combination with a progestin in COCs, the specific effects of
these estrogens alone on bone in premenopausal women are
not known. However, COCs do not decrease bone density
even in adolescents. A review of recent studies of COCs
containing 20 versus 30 mcg EE indicated that the lower
dose may not support peak bone mass acquisition in
adolescents [169]. However, overall, observational evidence
suggests that EE-based COCs have either a positive or
neutral effect on bone density and are associated with a
reduction in most markers of bone turnover [170]. In a 2-year
study of women taking either E2 (1.5 mg)/NOMAC (2.5 mg)
or EE (30 mcg)/LNG (150 mcg), neither treatment
negatively impacted bone mineral density [171].
718 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
6.7. Nervous system
ERs are found in parts of the brain stem and limbic system
that control mood, behavior, sex drive and autonomic function
[172]. Endogenous estrogens have been linked to several
movement disorders (including chorea), but the mechanism is
not known [172]. There is evidence linking decreasing E2
levels to premenstrual migraine headaches [173]. Estrogen
fluctuations represent trigger factors for migraine attacks;
however, the exact mechanisms and mediators underlying
these effects are largely unknown [174].
Estrogens increase seizure activity, whereas progestins
decrease this activity. COCs containing EE, for most
women, do not influence neurological or psychological
function. Some women may develop mild or moderate
depression or loss of libido [175], while other studies suggest
an improvement in mood [176].
6.8. Liver
Earlier studies with high-dose oral contraceptives had
suggested that the risk of liver tumors may be increased in
COC users. However, a detailed review of these observations
indicated that the incidence of liver disease was generally
low, and, more importantly, studies spanning over 27 years
showed no evidence of an increased risk of serious liver
disease in both current and former users of COCs [177].
The stimulatory effect of orally administered estrogens on
hepatic globulins and other proteins is well recognized.
However, most of the studies on the comparative effects of
different estrogens have been carried out in postmenopausal
women. Increases in SHBG, corticosteroid-binding globulin,
thyroid-binding globulin and angiotensinogen (also a
globulin) are achieved with increasing doses of EE and E2.
However, greater increases are found with EE compared
with E2 [178]. When the estrogen is combined with a
progestin, the stimulatory effect of the estrogen on SHBG
levels may be suppressed, depending on the androgenic
properties of the progestin. Variable effects of the estrogens
are observed in COC users on hemostatic proteins involved
in coagulation, as discussed earlier.
6.9. Skin
Low-dose COCs are effective in treating acne and
hirsutism. This effect is predominantly a consequence of
decreased circulating levels of free testosterone owing to the
pronounced increase in SHBG caused by the EE component
of COCs. The extent of the SHBG increase depends on the
amount of estrogen and type of progestin in the COC.
Formulations containing 30 to 35 mcg EE in combination
with one of the nonandrogenic progestins such as cyproter-
one acetate, norgestimate, desogestrel, gestodene or drospir-
enone increase SHBG levels considerably, thereby
decreasing free testosterone levels to very low concentra-
tions [179,180]. COCs containing the androgenic progestin
LNG also have a beneficial effect on acne and hirsutism,
even though high doses of LNG cause acne. Since the
androgenic properties of LNG cause a suppression of SHBG,
one would expect a higher level of free testosterone with
LNG-based low-dose COCs. However, free testosterone
levels achieved by LNG-containing COCs are similar to
those obtained with the nonandrogenic COCs [179]. This
effect is due to the strong impact of LNG on the HPO axis,
which causes a reduction in ovarian total testosterone
production. Consequently, free testosterone concentrations
become very low, even though SHBG levels are increased to
a relatively small extent. Presently, there are insufficient
data on the effectiveness of the new E2-based COCs on acne
and hirsutism.
7. Drug interactions with COCs
While it is important to understand the pharmacokinetic
and pharmacodynamic effects of estrogenic components, it is
essential to remember that they are often used in combination
with other drugs. Many drugs are also metabolized/
detoxified by the same cytochrome P450 enzymes that act
on endogenous estrogens, and can therefore alter the
circulating levels of these estrogens.
7.1. Anticonvulsants
Estrogens are metabolized by the hepatic cytochrome
P450 (CYP) system, specifically CYP3A4 [1]. Many anti-
convulsants (carbamazepine, phenobarbital and phenytoin)
can alter the activity of CYP isoenzymes in the liver.
Treatment of premenopausal epileptic women with enzyme-
inducing antiepileptic drugs (AEDs) can result in significant
abnormalities in reproductive hormone concentrations
[181,182]. In contrast, the concentrations of these agents in
women who received AEDs that do not alter CYP enzymes
(gabapentin or lamotrigine) were no different from non-
epileptic controls [181]. Newer AEDs, which do not induce
CYPs (levetiracetam, zonisamide, gabapentin and tiagabine),
do not appear to alter COC pharmacokinetics or plasma
concentrations [183]. Contraceptives containing EE can in
addition induce the activity of uridine-diphosphate glucur-
onosyltransferase and thus increase the rate of drug
glucuronidation, a mechanism proposed to be responsible
for the observed increase in renal excretion and reduced
therapeutic concentrations of the AED lamotrigine in women
using EE-based contraceptives [184]. Progestin-only con-
traceptives did not affect lamotrigine serum concentrations.
7.2. Antibiotics
Antibiotics do not appear to interfere with COC
effectiveness [185,186]. Rifampin is an exception because
it increases hepatic metabolism (via CYP450 enzyme) and
thus increases steroid metabolism resulting in decreased
COC hormone levels. Women prescribed rifampin concom-
itantly with COCs have a significant risk of contraceptive
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
failure [187]; therefore, women taking rifampin should use
other forms of contraception.
7.3. Smoking and drug–drug interactions
(contraindications)
Cigarette smoke causes lung cancer and is a significant
risk factor for the development of numerous cardiovascular
diseases and diabetes. The estrogenic activity of orally
administered hormone therapy in postmenopausal women
who were smokers may be impaired or even eliminated
completely [188,189], primarily through the effects of
smoking on enzymatic activity with resultant increased
metabolic clearance of the estrogens. Smoking diminishes
the effects of estrogen supplements on hot flashes and
urogenital symptoms, along with their positive effects on
lipid metabolism, and also reduces estrogen's ability to
prevent osteoporosis [189]. Women metabolize nicotine
significantly more quickly than men [190]. Nicotine
clearance is also higher in women taking oral contraceptives
than in those who do not. Among oral contraceptive users,
nicotine metabolism was accelerated among those taking
COCs and also in postmenopausal women who were using
only estrogen for hormone therapy. In women who used
progestin-only contraceptives, nicotine metabolism was not
altered. Nicotine metabolism was similar in postmenopausal
women who were not using estrogenic supplements and in
men [190]. These studies suggest that smoking can influence
the effect of estrogens and estrogen metabolism, and
estrogens also can influence the metabolism of other
compounds. In women who are cigarette smokers, COC
use can influence the prostacyclin/thromboxane balance
negatively compared with nonsmokers [191].
HIV-infected patients often receive a complex therapeutic
regimen that includes two or more antiretroviral agents and
several prophylactic drugs for protection against common
opportunistic pathogens. Understanding the interactions
between antiretrovirals and oral contraceptives is important,
as women of childbearing age represent a growing
proportion of people living with HIV.
Interactions between antiretroviral drugs and hormonal
contraceptives might alter the safety and effectiveness of
both the hormonal contraceptive and the antiretroviral drug
[132]. When healthy volunteers received a single dose of a
COC containing 50 mcg EE with ritonavir, mean peak
plasma EE concentration decreased by 32% and mean area
under the curve decreased by 41% compared with admin-
istration of the COC alone [192], suggesting an increased
risk of oral contraceptive failure. However, EE and LNG
levels were higher in HIV-positive women than in HIV-
negative women in Malawi [193], and COCs maintained
effectiveness in this small group of women treated with
nevirapine. These results suggest that the clinical outcomes
of COCs in women taking antiretroviral drugs could be
different depending on HIV status. The efficacy of E2-based
COCs remains to be investigated in these women.
719
8. Side effects of E2 and EE
Breast tenderness, headache, fluid retention (bloating)
and nausea are all recognized minor side effects of
exogenous estrogen used for contraception or menopausal
symptoms. Most documented side effects of estrogenic
therapy in young women are derived from studies of COCs.
Early reports of EE-related side effects often occurred as a
result of the use of very high doses of EE in COCs (initially
150 mcg daily, later reduced to 50 mcg daily) [194].
Lowering the dose of EE from 35 to 20 mcg resulted in
reduced symptoms of breast tenderness, nausea and
dizziness [5,195], but was associated with a higher incidence
of unscheduled bleeding [5] than COCs with a higher EE
dose. In a systematic review, no significant difference in
contraceptive efficacy was observed for COCs that contained
20 or 35 mcg EE [5]. When women who experienced
estrogen-related side effects while using COCs switched to
an estrogen-free progestin-only contraceptive, headache,
breast tenderness and nausea improved [196].
There were few differences in side effects in recent trials
comparing COCs with EE to those with E2 or E2V. No
differences were noted in most side effects, including weight
gain and headache, in a study comparing E2 (1.5 mg)/
NOMAC (2.5 mg) with EE (30 mcg)/drospirenone (3 mg)
[21]. Both drugs reduced acne from baseline, although more
participants in the E2/NOMAC arm than in the EE/
drospirenone reported acne (15% vs. 7%, respectively) at
the end of the 1-year trial. Also, more patients in the E2/
NOMAC arm reported an absence of withdrawal bleeding
ranging from 22% (cycle 4) to 31% (cycle 13) than those in
the EE/drospirenone arm (3% to 6%, without any particular
trend). Most side effects reported in a seven-cycle compar-
ative study of E2V/dienogest and EE/LNG were similar
between groups [18].
9. Adverse and serious effects associated with exogenous
administration of E2 and EE: risk assessment
9.1. Cardiovascular events
9.1.1. Stroke and myocardial infarction resulting from
arterial thromboembolic events
Although COCs increase the risk of ischemic stroke
[197,198] and MI [197], their risk may be overestimated
due to underlying disease such as hypertension or to
smoking rather than COC use alone [199,200]. Over 5
years, arterial thromboembolism (e.g., strokes, arterial
thrombosis) decreased in EE/drospirenone users but not
in EE/LNG users or nonusers [201]. Taken together, these
studies imply that there may be an increased risk of arterial
thromboembolism with EE, but it is small and may be
modified by the concomitant use of some progestins. No
data on the risk of arterial thromboembolism are available
for E2-based COCs.
720 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
9.1.2. VTE
VTE risk from COC use is highest in women with known
cardiovascular risk factors, including smoking, high BP,
diabetes, obesity, age, history of thrombosis or other
coagulation abnormalities [133,202–204]. Some studies
have suggested that COC formulations containing newer,
less androgenic progestins are associated with higher VTE
risk than older progestins [205,206]. However, in studies that
corrected for various confounding factors such as weight,
smoking status, alcohol use, age and duration of use, no
difference in VTE risk was seen between users of COCs
containing older and newer progestin types [201,207–210].
Differences between older and newer progestins in COCs
have been discounted owing to the methodological problems
with many studies [211,212].
The effect of progestins on VTE is controversial as of this
writing. As discussed earlier, E2 has less of a stimulatory
effect than EE on the hepatic system to increase the
production of procoagulant proteins. COCs containing E2
or E2V have not been in widespread use for a long enough
time to determine whether they have less of an effect on
cardiovascular events than EE-based COCs.
9.2. Cancer
9.2.1. Breast cancer
The potential role of estrogens in breast cancer was first
suggested by Lacassagne [213] when he demonstrated that
the administration of E1 to male mice induced mammary
cancer. This, coupled with the much earlier observation of
Beatson [214] that oophorectomy had a beneficial effect in
two women who developed breast cancer, evoked the
hypothesis/belief that estrogens (E2) play an etiological
role in breast cancer in women. The observation that bilateral
oophorectomy reduces the risk of breast cancer has been
shown in epidemiologic studies [215,216]. This favorable
effect of oophorectomy on breast cancer has been of
continuing interest and concern regarding the role and
relationship of endogenous estrogens that may affect the risk
and development of breast cancer. It is well established that,
in the human breast, estrogens increase fat deposition, the
development of stromal tissue, the growth of an extensive
ductile system and, to a lesser extent, the development of
lobules and alveoli. However, progesterone and prolactin
also are involved in the key growth and function of those
structures. Therefore, it is highly speculative to infer that the
decrease in breast cancer risk following oophorectomy is
specific to levels of estrogen only and to assume that
estrogens are solely involved in the etiology of breast cancer.
In the past decades, the persevering concern about the effect
of estrogen on breast cancer risk has led to numerous
epidemiologic studies with no firm conclusions and many
elusive unanswered questions. It is important to note that the
early high-dose COCs had numerous side effects and have
now been replaced by significantly lower-estrogen-dose
formulations. These more recently formulated contraceptive
pills and their possible implication in the incidence of breast
cancer are briefly reviewed here.
A number of early epidemiologic studies investigated the
effect(s) of COCs on breast cancer risk; some studies
indicated no significant increase in the risk of breast cancer,
while others found the opposite. In general, these findings
were reassuring in that the increase in the risk of breast
cancer was small. Essentially, all of the early studies were
reanalyzed in a very large meta-analysis carried out by the
Collaborative Group on Hormonal Factors in Breast Cancer.
Data from 54 studies were reanalyzed. Over 53,000 women
from 26 countries with breast cancer and over 100,000
women without breast cancer were assessed for the risk of
breast cancer and use of various formulations of COCs
[217,218]. In this analysis, irrespective of the dose of
estrogen (b 50 to N 50 mcg), the RR of breast cancer in ever
users of COCs was statistically, albeit slightly, elevated (RR,
1.07; CI, 1.03–1.10). More importantly, this small increase
in the risk of breast cancer was observed in either women
who were current COC users or those who had started use at
a young age (before age 20 years). Furthermore, in this group
of women, the risk of metastatic disease compared with
localized tumors was significantly reduced (RR, 0.88; CI,
0.81–0.95). These data also suggest that, after stopping the
intake of COCs, the protective effect against metastatic
disease persists posttreatment.
In contrast to the above study, a Canadian case–control
study assessed the relation of use of COCs to the risk of
breast cancer in women under the age of 70 years and
showed a beneficial effect [219]. The women in this study
had used COCs for different durations ranging from less than
1 year to more than 15 years prior to the study. The results
indicate that the RR estimated for 5 or more years of use
followed by an interval of more than 15 years was 0.5 (CI,
0.3–0.38) or a 50% reduced risk of breast cancer. A case–
control study of 4575 American women aged 35 to 64 years
with breast cancer and 4682 controls estimated the risk of
breast cancer among former and current users of COCs
[220]. The results show no increased risk in both current
users (RR, 1.0; CI, 0.8–1.3) and past users (RR, 0.9; CI, 0.8–
1.0). The RR did not appear to increase with longer duration
of COC use or higher dose of estrogen, or in women who had
a family history of breast cancer or in those who had initiated
use at a young age.
Since women with a history of benign breast disease
(BBD) are thought to be at a higher risk of breast cancer
[221,222], a number of studies assessed the relationship
between BBD and COC use. The results from a number of
studies suggest a protective effect of COCs on all types of
BBD [223,224]. Thus, in a Canadian cohort study
investigating the association between COC formulations
that were in use 15 to 20 years ago, protection against
proliferative BBD was observed. Greater reduction was seen
with increasing duration of COC use, with incidence rate
ratios of 0.64 (CI, 0.47–0.87) [225]. Similarly, a large
Oxford Family Planning Association Study that included
 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
17,032 women who had used various methods of contra-
ception including COCs containing N 50, 50 and b 50 mcg of
estrogen not only confirmed the previously observed
protective effect against BBD with the earlier formulations
of COCs containing 50 or N 50 mcg of estrogen but also
found the same degree of protection with newer formulations
containing b 50 mcg estrogen [226].
Although the Collaborative Group Study [217,218]
discussed above showed that recent users of COCs were
associated with a small risk increase that was not altered by a
family history of breast cancer, concern is still prevalent of
an increased risk of breast cancer in COC users with BRCA1
and BRCA2 mutations. In this regard, one study based on a
small number of cases of women with these mutations did
not observe a statistically significant increase in risk of breast
cancer with COCs [227]. In contrast, a large case–control
study showed that BRCA1 mutation carriers had a small
increased risk in women who had used COCs for at least 5
years before the age of 30 years and in those who developed
breast cancer before the age of 40 years [228]. However, a
multicountry population-based study of Caucasian women,
consisting of 1156 women with invasive breast cancer cases
diagnosed before the age of 40 years, concluded that users of
the more recent formulations of COCs, which contained
lower amounts of estrogen, showed no increase in the risk of
early onset of breast cancer for both BRCA1 and BRCA2
mutation carriers. Interestingly, they showed that carriers of
the BRCA1 mutation had a significantly reduced risk of
breast cancer with COC use with an OR of 0.22 (CI, 0.10–
0.49). The OR of breast cancer with COC use in women with
the BRCA2 mutation was 1.02 (CI, 0.34–3.09), whereas, in
noncarriers, it was 0.93 (CI, 0.69–1.24). The authors also
concluded that current COC formulations did not appear to
exacerbate the risk of ovarian cancer in carriers of these two
BRCA mutations [229].
As discussed above, the implication of hormones,
particularly estrogens, in the etiology of breast cancer has
been suggested for decades; however, their role is still
unclear in spite of numerous studies dealing with COCs. The
evidence regarding breast cancer mortality in COC users
found in two large British cohort studies shows that there is
no increase in breast cancer mortality [230–232].
Considering the fairly large body of epidemiological data
which generally indicate that the risk of breast cancer in
COC users is not increased, perception to the contrary still
persists. This raises an important question as to whether
nonrandomized prospective studies can ever provide a
definite answer when the magnitude of risk is low.
Interestingly, Shapiro [233] in his detailed review of the
large meta-analysis [218] concluded the following: “Finally,
this exercise serves to demonstrate that relative risk point
estimates derived from nonexperimental studies are, by their
nature, crude and imprecise. Given the small amounts of bias
that it takes to distort such estimates, their expression to more
than one decimal place is pseudoprecision. Yet, for low-
magnitude associations such as in the collaborative reana-
721
lysis and in the examples mentioned above, this practice is
common, perhaps in the mistaken belief that such pseudo-
precision somehow confers validity to associations that are
not, in fact, demonstrably valid.” Thus, the saga continues,
and the valid concerns in the minds of women using COCs
will persist.
9.2.2. Endometrial and ovarian cancers
EE-based COC use is associated with a 50% decrease in
the incidence of endometrial cancer risk that persists for at
least 15 years after stopping the COC [234,235]. Further,
COCs have been shown to be protective for all three major
histologic subtypes of endometrial cancer (adenocarcinoma,
adenoacanthoma and adenosquamous cancers) [236].
EE-based COCs have a protective effect against ovarian
cancer, one of the most lethal of female reproductive tract
cancers. Compared to non-COC users, the risk of developing
epithelial ovarian cancer of all histologic subtypes is
decreased by 40% in users of COCs [237]. The protective
effect increases with duration of use and continues for 20 or
more years after the treatment is stopped.
9.2.3. Other cancers
In addition to the protective effect of COCs on endometrial
and ovarian cancers discussed above, EE-based COCs
generally have a protective or neutral effect on other cancers,
with the exception of cervical cancer. Studies show that the
risk for dysplasia and carcinoma in situ of the uterine cervix
increases with the use of COCs for longer than 5 years [238].
However, confounding factors pertaining to the risk of
cervical cancer are difficult to control; therefore, conclusions
about this risk are not definite.
A recent large cohort study [239] by the RCGP found that
the risk of all cancers among ever users of COCs was lower
compared with never users (adjusted relative risk ratio, 0.85;
95% CI, 0.78–0.93).
9.2.4. Mortality
In spite of the known risks of COCs containing EE, COCs
overall have an excellent safety record. The RCGP found
that COC ever users had a significantly lower death rate from
any cause (RR, 0.88; 95% CI, 0.82–0.93) compared with
never users [239]. Ever users also had significantly lower
rates of death from all cancers, including large bowel/rectum,
uterine body, ovarian and all gynecological cancers,
compared with never users. Given the recent approval of
COCs with E2, no large outcome studies have compared
COCs with EE to those containing E2. Whether E2-based
COCs will show the same or an improved safety profile
remains to be established.
10. Conclusions
Women have been taking COCs containing EE for more
than 50 years. Overall, EE-containing COCs have a very
favorable safety profile; however, there are some health
722 F.Z. Stanczyk et al. / Contraception 87 (2013) 706–727
concerns and side effects that still need to be addressed. To
date, reduction in the dose of EE in currently available COCs
has significantly improved COC safety and tolerability, but
efforts to further reduce EE- and COC-related risks continue.
E2 and E2V in combination with a progestin have, in a
relatively small number of studies, shown to provide
contraceptive efficacy that is similar to low-dose COCs
with EE. These recent E2 formulations also appear to have
acceptable cycle control and an acceptable safety profile.
However, long-term studies are needed to confirm these
observations and to determine whether there are any clinical
advantages in using E2 versus EE.
Acknowledgments
The authors would like to thank A. Peter Morello III,
Ph.D.; Alex Loeb, Ph.D.; and Tove Anderson, Ph.D., of
Evidence Scientific Solutions for professional editing
services which were supported by Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc. No funding was
provided to the authors for this review.
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