CONTRACEPTION
Combined hormonal
contraception
Anna Glasier
The combined oral contraceptive pill (COCP) was introduced in
the early 1960s and is currently used by more than 60 million
women worldwide. In the UK, 25% of women using a revers-
ible method of contraception take an oral contraceptive pill. The
COCP is popular because of its efficacy, ease of use and additional
health benefits beyond those of contraception. In recent years,
new delivery systems for combined hormonal contraception have
become available. The contraceptive patch Evra was marketed in
the UK in 2004. The combined contraceptive vaginal ring Nuvar-
ing is available in much of Europe and in the USA. There are no
plans to market the combined injection Lunelle in the UK. The
mechanism of action and efficacy of these relatively new delivery
systems are similar to those of the COCP. Few data are available
on the long-term risks, but it is sensible to assume that they too
are no different from the COCP.
Available preparations
Combined hormonal contraceptives contain both estrogen (usually
ethinylestradiol) and a progestogen (a synthetic compound that
behaves like progesterone).
Combined oral contraceptive pill
Estrogen: the dose of estrogen used in the COCP is 15–50 µg; most
women now use so-called ‘low-dose pills’ containing 30–35 µg.
Low-dose pills are potentially safer, because the cardiovascular
risks of the COCP result mainly from estrogen. However, the lower
the dose of estrogen, the higher the risk of poor cycle control,
breakthrough bleeding and, at least theoretically, pregnancy if
compliance is poor. This is reflected in the new rules for missed
pills, which distinguish between pills containing less than 30 µg of
ethinylestradiol and those containing 30 µg or more (Figure 1).
Anna Glasier is Honorary Professor in the Department of Obstetrics and
Gynaecology at the University of Edinburgh, UK and in the Department
of Public Health and Policy at the University of London School of Hygiene
and Tropical Medicine, London, and Lead Clinician for Sexual Health in
NHS Lothian. She qualified from the University of Bristol, and trained in
obstetrics and gynaecology, specializing in reproductive medicine. Her
research interests are contraception, including emergency contraception,
and reproductive health care. Conflicts of interest: none declared.
This article has been reproduced from: Medicine 2006; 34(1): 1–5.
WOMEN’S HEALTH MEDICINE 3:6
What’s new ?
• Transdermal, vaginal and injectable methods
containing both estrogen and progestogen are now
available
• Amenorrhoea is becoming more acceptable among
women using hormonal contraception
• WHO medical eligibility criteria are replacing the
concept of relative and absolute contraindications to
use of all contraceptive methods
• The risk of cervical cancer is increased in women using
the combined pill, particularly if they have persistent
human papillomavirus infection
Progestogens used in currently available COCPs are divided into
four groups:
• first-generation progestogens (norethindrone)
• second-generation norgestrel derivatives (e.g. levonorgestrel)
• third-generation progestogens (e.g. gestodene, desogestrel,
norgestimate)
• the newest progestogen, drospirenone (has anti-androgenic and
antimineralocorticoid activity; the term ‘fourth generation’ is
avoided by the manufacturer).
Different progestogens differ in potency and thus contraceptive
effectiveness is achieved at different doses. At equivalent contra-
ceptive efficacies, the progestogens are said to have slightly differ-
ent side-effects, but the evidence is unconvincing, except possibly
for side-effects clearly associated with relative differences in andro-
genicity (e.g. acne). The anti-androgenic properties of drospirenone
may make it particularly beneficial for acne and hirsutism.
Formulations: classically, the COCP is taken for 21 days followed by
a 7-day break (the pill-free interval, PFI), when withdrawal bleed-
ing usually occurs. Combined pills are available in monophasic
preparations (in which every pill in the packet contains the same
dose of steroids), and biphasic and triphasic preparations (in which
the dose of both estrogen and progestogen changes once or twice
over the 21-day period). Biphasic and triphasic pills were intro-
duced to reduce the total dose of progestogens, and in the belief
that a regimen that mimicked the normal cycle would produce
better cycle control. However, there is no evidence for better cycle
control, and some women find such preparations confusing, par-
ticularly when they want to take two packets of pills consecutively
to postpone menstruation. In an attempt to improve compliance,
everyday preparations are used widely in the USA and Australia.
These regimens involve the taking of inactive tablets, rather than
7 days without pills.
In the USA, an 84-day packet of pills (followed by a 7-day PFI)
is marketed as Seasonale. Only four withdrawal bleeds per year is
a pattern increasingly popular with many European women and
can be achieved simply by taking 21-day packets of pills consecu-
tively.
One manufacturer is now evaluating a combined pill which is
taken continuously with no breaks and therefore with no with-
drawal bleeds.
257 © 2006 Elsevier Ltd
 CONTRACEPTION
Guidance for women who have missed pills
If one or two 30–35 µg ethinylestradiol pills
have been missed at any time
or
One 20 µg ethinylestradiol pill is missed
She should take the most recent missed pill as soon as
she remembers
She should continue taking the remaining pills daily at
her usual time1
She does not require additional contraceptive
protection
She does not require emergency contraception
1Depending on when she remembers her missed pill, she may take two pills on the same day (one at the moment of remembering and the other at the regular time)
or even at the same time
Figure 1
Combined contraceptive patch
Only one contraceptive patch is currently available. Evra is
20 cm2 in area and delivers 20 µg of ethinylestradiol and 150 µg
of norelgestromin (17-deacetylnorgestimate) per day. Each patch
lasts 7 days; three patches are used consecutively, followed by a
placebo patch or patch-free interval in week four, when withdrawal
bleeding occurs. Contraceptive protection lasts for up to 10 days,
allowing for errors in changing the patch. In a randomized trial
comparing the patch with a COCP, there was no significant differ-
ence in effectiveness; overall pearl indices were 1.24/100 women-
years for the patch and 2.18/100 women-years for the COCP. The
efficacy may be reduced in heavier women. Bleeding patterns and
side-effects are similar to those associated with the COCP.
Combined contraceptive vaginal ring
Nuvaring releases 15 µg of ethinylestradiol and 120 µg of
etonorgestrel per day and is now licensed in much of Europe. The
ring is made of soft ethylene-vinyl-acetate co-polymer and meas-
ures 54 mm in diameter. It is designed to last for 3 weeks; a 7-day
ring-free interval is associated with bleeding patterns that appear
superior to those associated with the COCP. In all other respects,
including efficacy, the ring is no different from the COCP.
WOMEN’S HEALTH MEDICINE 3:6
If three or more 30–35 µg ethinylestradiol pills have been
missed at any time
or
Two or more 20 µg ethinylestradiol pills are missed
She should take the most recent missed pill as soon as she remembers
She should continue taking the remaining pills daily at her usual time 1
She should be advised to use condoms or abstain from sex until she has
taken pills for 7 consecutive days
In addition (because extending the pill-free interval is risky)
If pills are missed in week 1 If pills are missed in week 3
(days 1–7) (because the pill-free (days 15–21) (to avoid extending
interval has been extended) the pill-free interval)
Emergency contraception should She should finish the pills in her
be considered if she had current pack and start a new
unprotected sex in the pill-free pack on the next day, thereby
interval or in week 1 omitting the pill-free interval
Combined injectable contraceptive
A once-monthly injectable contraceptive containing 25 mg of
medroxyprogesterone acetate and 5 mg of estradiol cypionate
(Lunelle) is available in some parts of the world, but not in the
UK. Injections are administered intramuscularly every 28 days.
Bleeding episodes occur 18–22 days after injection when estrogen
concentrations decline to 50 pg/ml or less. About 70% of women
experience one bleeding episode per month.
Mode of action
Combined hormonal contraception acts mainly by inhibiting
ovulation. The estrogen component inhibits secretion of pituitary
follicle-stimulating hormone, thereby suppressing the develop-
ment of ovarian follicles; progestogen inhibits the development
of the luteinizing hormone surge. Other mechanisms of action of
combined hormonal contraception are shown in Table 1.
In some women, the 7-day hormone-free interval is long enough
to allow follicle growth; on the last day of the PFI, 25% of women
using the COCP exhibit ultrasonographical evidence of follicles of
10 mm in diameter. If the PFI is extended beyond 7 days, these
follicles continue to grow and, despite restarting the pill, ovula-
tion may occur. The same is likely to be true of the hormone-free
258 © 2006 Elsevier Ltd
 CONTRACEPTION
Mechanisms of action of combined oral
contraceptives
• Inhibition of ovulation
• Changes in cervical mucus that interfere with sperm transport
• Tubal motility may be altered
• Atrophy of endometrium
• Uterine receptivity essential for successful implantation may
be impaired
Table 1
interval following patch or ring use. In women who appear to have
conceived as a result of a genuine COCP failure (rather than as a
result of an error in pill-taking) and who wish to continue using
the COCP after the pregnancy is over, the PFI can be shortened to
4 or 5 days to ensure suppression of follicular development. Some
brands of low-dose COCP have a shorter PFI as standard.
Because the risks of the COCP are mainly from estrogen, manu-
facturers have steadily reduced the dose. In recognition of the risk
of compromising contraceptive efficacy, one formulation (Mircette,
currently available only in the USA) comprises 21 days of 20 µg
ethinylestradiol in combination with desogestrel, but includes five
daily doses of 10 µg ethinylestradiol alone during the ‘pill-free’
week to maintain suppression of follicle growth.
Efficacy
When used correctly, combined hormonal contraceptives are
almost 100% effective. The failure rate during ‘perfect’ use is
0.1%. In practice, methods of contraception that make demands
of users have a higher failure rate, because mistakes are made
during ‘typical use’. Because of errors in pill-taking, the failure
rate associated with typical use of the COCP is about 8%. There
is evidence that use of the patch or ring may be less demanding,
so typical-use failure rates (not yet available for either method)
may be lower. This should be a clear advantage for the combined
injectable contraceptive.
Contraindications
Absolute contraindications (WHOMEC category 4 conditions)
to the COCP are listed in Figure 3. Relative contraindications
(WHOMEC category 3 conditions) include serious or multiple risk
factors for arterial disease, including hypertension, family history,
diabetes mellitus, smoking, age over 35 years, obesity and migraine
(Table 2). The Faculty of Family Planning & Reproductive Health-
care adapted the WHOMEC for use in the UK. The categories are
essentially the same but a few additional conditions have been
added – the UKMEC is available on www.ffprhc.org.uk.
Women with hyperprolactinaemia who want to avoid pregnancy
should be advised to use progestogen-only contraception, because
estrogen stimulates lactotrophs (prolactin-secreting cells in the
pituitary gland), thereby increasing the prolactin concentration.
Risks and side-effects
WOMEN’S HEALTH MEDICINE 3:6
WHO medical eligibility criteria category 3 and 4
conditions for combined oral contraception
Category 3 conditions
• Breast-feeding 6 weeks to 6 months post-partum
• Before 3 weeks after childbirth
• Smoking < 15 cigarettes/day and > 35 years of age
• Adequate controlled hypertension
• Blood pressure > 140/90 mm Hg, < 160/100 mm Hg
• Severe hyperlipidaemia
• Non-migraine with aura and > 35 years of age
• Previous breast cancer – 5 years without recurrence
• Current or medically treated gallbladder disease
• Past combined oral contraception-related cholestasis
• Mild cirrhosis
Category 3/4 conditions
• Multiple risk factors for cardiovascular disease
• Diabetes with retinopathy, nephropathy, neuropathy or other
vascular disease, or of > 20 years’ duration
Category 4 conditions
• Breast-feeding before 6 weeks post-partum
• Smoking > 15 cigarettes/day and > 35 years of age
• Blood pressure > 160/100 mm Hg
• Hypertension with vascular disease
• History of or current deep vein thrombosis
• Major surgery with prolonged immobilization
• History of or current myocardial infarction
• History of stroke
• Complicated valvular heart disease
• Migraine with aura
• Current breast cancer
• Severe cirrhosis
• Liver tumour
Table 2
Combined hormonal contraception has an effect on almost every
system in the body. Most side-effects are minor; mood change,
weight gain or fluid retention, nausea and vomiting, headache,
loss of libido, mastalgia, breast enlargement and greasy skin are
common complaints that also occur in the absence of contraceptive
use. Many improve or disappear within 3–6 months of starting
the method, but side-effects often lead to discontinuation. Some
side-effects may be alleviated by changing to a different delivery
system. The patch, for example, should be associated with less
nausea. In women who use the COCP, the dose of estrogen or type
of progestogen can be altered by changing to a different brand
of pill, and it is worth trying this if time alone does not solve
the problem. Chloasma is much less common and is definitely
related to steroid hormones. It can also occur with progestogen-
only methods.
Serious side-effects involve mainly the cardiovascular system.
Combined hormonal contraception affects both the venous (venous
thromboembolism (VTE)) and the arterial (myocardial infarction
(MI), cerebrovascular accident) circulation. Although the aetiology
259 © 2006 Elsevier Ltd
 CONTRACEPTION
and epidemiology of venous and arterial disease differ, in both
cases the increased risk appears to be related to an increased
thrombotic tendency. Contraceptive steroids are metabolized by
the liver and affect the metabolism of carbohydrates, lipids, plasma
proteins, amino acids, vitamins and clotting factors. Changes in
clotting factors create a tendency to hypercoagulability, which is
partly balanced by an increase in fibrinolysis. The adverse effect
on clotting is related to the dose of estrogen; low-dose pills are
associated with a reduced risk compared with pills containing
50 µg of ethinylestradiol.
In a recent analysis of 25 years’ follow-up of 46,000 women
who took part in the Royal College of General Practitioners (RCGP)
Oral Contraceptive Study (comparing 517,519 years of COCP use
with 335,998 years of never-use), the risk of death from all causes
was similar in ever-users and never-users of oral contraception.
In current or recent users, however, there was an increase in the
relative risk of death from two conditions – cervical cancer (rela-
tive risk 2.5) and haemorrhagic stroke (1.9).
Venous disease
The COCP is associated with a threefold increase in the relative
risk of VTE. Risk is unaffected by age, smoking and duration of
COCP use, but is higher in obese women (body mass index, BMI
> 30 kg/m2) and in women with a history of pregnancy-induced
hypertension. Opinion varies acrimoniously on the validity and
interpretation of several studies published in the mid-1990s show-
ing differing VTE risk with different types of progestogen. On
balance, most experts agree that the difference in risk of VTE is
real but small. COCPs containing the third-generation progestogen
gestodene or desogestrel carry about a twofold increased risk of
VTE compared with pills containing levonorgestrel. Although the
reason for this difference is unclear, it is known that oral contra-
ceptive use reduces the efficiency with which activated protein C
down-regulates in vitro thrombin formation, and this phenomenon
appears to be more pronounced in women using a COCP contain-
ing desogestrel rather than levonorgestrel.
The absolute risk of VTE in COCP users is very low
(15/10,000 woman-years) and considerably less than that during
pregnancy (60/10,000 woman-years). The risk returns to normal
within 3 months of stopping the COCP. The Committee on Safety of
Medicines warns that women should be informed of the increased
risk of VTE when third-generation pills are prescribed. It is possible
that COCPs containing anti-androgens may be associated with an
even higher risk of VTE. This certainly appears to be the case for
Dianette, a combination of ethinylestradiol and cyproterone acetate
licensed for treatment of hirsutism and severe acne that acts as
a combined oral contraceptive. There is no reason to believe that
the risk of VTE is any different with other routes of administration
of combined hormonal contraception (patch, ring or injectable).
Women with inherited thrombophilias (e.g. factor V Leiden)
are at increased risk of VTE, and a family history of VTE is an
indication for testing for various thrombophilias. Population-level
screening is considered neither practical nor economical.
Arterial disease
Arterial disease in COCP users is much more serious than venous
disease, though the absolute risk of MI and stroke in young
women is tiny. There is widespread agreement that the risk of MI
is increased in women who take the COCP and smoke or have
WOMEN’S HEALTH MEDICINE 3:6
hypertension, but the relationship between MI and COCP use is
controversial in women with no other risk factors.
• A recent meta-analysis of 23 studies concluded that the risk
of MI was increased in current COCP users vs never-users (odds
ratio 2.48, 95% CI 1.91–3.22).
• The risk in past-users was not increased, nor was the risk in
women using third-generation COCPs or COCPs containing 20 µg
of ethinylestradiol.
• The risk of MI was increased in women using second-generation
COCPs, and in smokers (by nine times) and women with
hypertension (tenfold).
The risk of stroke attributable to COCP use is small. The rela-
tive risk of haemorrhagic stroke is not increased in women under
35 years of age and is only slightly increased in older women. The
risk of ischaemic stroke is slightly increased (relative risk 1.5) and
is also slightly higher in the over-35s. Smoking and hypertension
increase the risk of stroke by tenfold and threefold, respectively.
Migraine
Women who have migraine with aura may be at increased risk
of stroke. Migraine with aura is a category 4 condition for use of
combined hormonal contraception.
Breast cancer
Overviews of the risks of COCPs are dominated by breast cancer.
Data are difficult to interpret because COCP formulations and
patterns of reproduction (particularly age at first pregnancy) have
changed with time. A meta-analysis of 54 studies involving more
than 53,000 women with breast cancer and 100,000 controls con-
cluded that use of the COCP was associated with a small increased
risk of breast cancer that persisted for 10 years after stopping the
COCP. The relative risk was 1.24 in current users, 1.16 1–4 years
after stopping and 1.07 5–9 years after stopping. After 10 years,
the relative risk was the same as that in never-users. Although the
relative risk was higher in women who started taking the COCP
at a young age (because breast cancer is uncommon in this age
group), there was little added effect from the duration of use, or
the dose or type of hormone. Women who had ever used the COCP
were significantly less likely (relative risk 0.88) than never-users
to develop cancer that spread beyond the breast, even if they had
stopped the COCP more than 10 years earlier. In the 25-year RCGP
follow-up study, ever-users were not more likely to die from breast
cancer than never-users.
A large case-control study from the USA involving 8000 women
(published after the 1996 meta-analysis) suggested no increase in
breast cancer risk (relative risk 1.0, 95% CI 0.8–1.3); however, the
upper limit of the confidence intervals is in line with the findings of
the much larger meta-analysis. Again, the association with breast
cancer is probably independent of the route of administration of
the contraceptive method.
The relationship between the COCP and breast cancer is dif-
ficult to explain, because the risk appears to increase soon after
exposure, does not increase with duration of use, and returns to
normal after 10 years of no exposure. It has been suggested that
starting the COCP may accelerate the appearance of breast cancer in
susceptible women. It is also possible that tumours are diagnosed
earlier in women who are using the COCP, though it is difficult
to explain why a tendency to earlier diagnosis would persist for
years after stopping. A biological effect of combined hormonal
260 © 2006 Elsevier Ltd
 CONTRACEPTION
contraception has not been excluded.
Cervical cancer
Data on the risk of cervical cancer in COCP users are difficult to
interpret, because barrier methods confer some protection and the
aetiology of cervical cancer is connected with sexual activity. In
the 25-year follow-up study, the relative risk of dying from cervical
cancer was 2.5 in ever-users. A meta-analysis of ten case-control
studies showed an increased risk of cervical cancer in women
with persistent human papillomavirus infection using hormonal
contraception. The relative risk was 2.8 after 5 years of use of the
COCP and 4.0 after 10 years.
Liver cancer
Benign hepatic adenoma is an uncommon consequence of COCP
use. In countries where hepatocellular carcinoma is rare, this
disease is occasionally associated with the COCP. In populations
where liver cancer is common (e.g. the Far East), short-term use of
COCPs does not affect the incidence of hepatocellular carcinoma;
data on long-term use are scarce.
Practical prescribing
History: a full history, including family history, should be taken to
exclude risk factors that might contraindicate combined hormonal
contraception use or indicate further investigations.
Examination: blood pressure should be measured, and it may
be helpful to record baseline weight. BMI of more than 30 kg/m2
is considered a relative contraindication to combined hormo-
nal contraception, and BMI more than 40 kg/m2 is an absolute
contraindication because of the increased risk of CVD.
Pelvic examination is not routinely indicated at the first (or any)
visit unless gynaecological pathology is suspected. Women do not
like pelvic examinations and some, particularly the young, may be
deterred from starting or continuing with the COCP if examination
is seen as a prerequisite. Breast examination is also unnecessary
unless the woman has symptoms of breast disease. Cervical smears
should be taken in accordance with national policy.
Choice of preparation: new users should usually start with a
low-dose (30–35 µg) pill containing a second-generation pro-
gestogen. If breakthrough bleeding occurs and persists beyond
the first 3 months, and a gynaecological cause is excluded, a
COCP containing a higher dose of estrogen or a different type of
progestogen may be tried.
Women taking long-term enzyme-inducing drugs (e.g. some
anticonvulsants) should use a preparation containing 50 µg of
estrogen, to ensure best efficacy (this may necessitate taking
two pills each day, one containing 30 µg and the other 20 µg of
ethinylestradiol, if a 50 µg preparation is not available).
The patch should be considered if nausea or vomiting is a per-
sistent side-effect of pill use or if there is a potential problem with
oral absorption. The patch may also be useful in women who want
to use combined hormonal contraception, but who have difficulty
remembering to take a pill every day.
Progestogen-only contraception may be considered in women
with contraindications to the COCP.
WOMEN’S HEALTH MEDICINE 3:6
Information: women should be carefully instructed how to use
the COCP and what to do when pills are forgotten (Figure 1).
Many women choose (or are ‘advised’) to take a break from using
the COCP for a few months. Although most cardiovascular risks
decrease when the pill is stopped, they recur as soon as it is started
again, and unplanned pregnancies commonly occur during such
breaks. Most women who stop the COCP regain normal fertility
within 3 months. Secondary, so-called ‘post-pill’ amenorrhoea is
almost always the result of abnormalities that were present before
the COCP was started (e.g. polycystic ovary syndrome), but which
were masked by regular artificial withdrawal bleeds.
There is no evidence for any adverse effect on the fetus as a
result of previous COCP use. When conception occurs during COCP
use, the risk of teratogenesis is low or non-existent. 
FURTHER READING
Beral V, Hermon C, Kay C et al. Mortality associated with oral
contraceptive use: 25 year follow up of a cohort of 46,000
women from Royal College of General Practitioners’ Oral
Contraception Study. BMJ 1999; 318: 96–100.
Etminan M, Takkouche B, Isorna F C et al. Risk of ischaemic stroke
in people with migraine: systematic review and meta-analysis
of observational studies. BMJ 2005; 330: 63–5.
Faculty of Family Planning and Reproductive Health Care Clinical
Effectiveness Unit. FFPRHC guidance (October 2003) first
prescription of combined oral contraception. J Fam Plann
Reprod Health Care 2003; 29: 209–23.
Khader Y S, Rice J, John L et al. Oral contraceptive use and risk of
myocardial infarction: a meta-analysis. Contraception 2003;
68: 11–17.
Marchbanks P A, McDonald J A, Wilson H G et al. Oral
contraceptives and the risk of breast cancer. N Eng J Med
2002; 346: 2025–32.
O’Brien P A. The third generation oral contraceptive controversy.
BMJ 1999; 319: 795–6.
Rosing J, Middeldorp S, Curvers J et al. Low-dose oral
contraceptives and acquired resistance to activated protein C:
a randomised cross-over study. Lancet 1999; 354: 2036–40.
Skegg D C G. Third generation oral contraceptives. BMJ 2000; 321:
190–1.
WHO. Improving access to quality care in family planning. Selected
practice recommendations for contraceptive use. Geneva:
WHO, 2005.
WHO. Improving access to quality care in family planning. Medical
eligibility criteria for contraceptive use. Geneva: WHO, 2004.
WHO. Cardiovascular disease and steroid hormone contraception.
Report of a scientific group. WHO Tech Rep Ser 1998; 877.
WHO. Oral contraceptives and neoplasia. WHO Tech Rep Ser 1992;
817.
261 © 2006 Elsevier Ltd