Clinical Pharmacology and Therapeutics

FEMALE REPRODUCTIVE ENDOCRINOLOGY 309
release by the pituitary via negative feedback on the hypothalamus.
This prevents the mid-cycle rise in LH which triggers
ovulation.
Progestogens currently used in combined oral contraceptives
include desogestrel, gestodene and norgestimate. These
‘third-generation’ progestogens are only weak anti-oestrogens,
have less androgenic activity than their predecessors (norethisterone,
levonorgestrel and ethynodiol) and are associated with
less disturbance of lipoprotein metabolism. However, desogestrel
and gestadene have been associated with an increased
risk of venous thrombo-embolism.
Endocrine effects of the combined oral contraceptive include:
1. prevention of the normal premenstrual rise and mid-cycle
peaks of LH and FSH and of the rise in progesterone
during the luteal phase;
2. increased hepatic synthesis of proteins, including thyroidbinding
globulin, ceruloplasmin, transferrin, coagulation
factors and renin substrate, while increased fibrinogen
synthesis can raise the erythrocyte sedimentation rate;
3. reduced carbohydrate tolerance;
4. decreased albumin and haptoglobulin synthesis.
Adverse effects of the COC
The overall acceptability of the combined pill is around 80%
and minor side effects can often be controlled by a change in
preparation. Users have an increased risk of venous thromboembolic
disease, this risk being greatest in women over
35 years of age, especially if they smoke cigarettes, are obese
and have used oral contraceptives for five years or more continuously.
The increased risk of venous thrombo-embolism
(VTE) has made it desirable to reduce the oestrogen dose as
much as possible. Progestogen-only pills may be appropriate
in women at higher risk of thrombotic disease.
In healthy non-pregnant women not taking an oral contraceptive,
the incidence of VTE is about five cases per 100 000
women per year. For those using the COC containing a secondgeneration
progestogen such as levonorgestrel, the incidence
is 15 per 100 000 women per year of use. Some studies have
shown a greater risk of VTE in women who are using COC
preparations that contain third-generation progestogens, such
as desogestrel and gestodene, reporting incidences of about 25
per 100 000 women per year of use. However, as the overall
risk is still very small and well below the risk associated with
pregnancy, provided that women are well informed about the
relative risks and accept them, the choice of a COC should be
made jointly by the prescriber and the woman concerned in
light of individual medical history and any contraindications.
Increased blood pressure is common with the pill, and is clinically
significant in about 5% of patients. When medication is
stopped, the blood pressure usually falls to the pretreatment
value. In normotensive non-smoking women without other risk
factors for vascular disease, there is no upper age limit on using
the combined oral contraceptive, but it is prudent to use the lowest
effective dose of oestrogen, especially in women aged
35 years or over. Mesenteric artery thrombosis and small bowel
ischaemia, and hepatic vein thrombosis and Budd–Chiari
syndrome are rare but serious adverse events linked to the use
of combined oral contraception. These cardiovascular adverse
effects are related to oestrogen. Jaundice similar to that of pregnancy
cholestasis can occur, usually in the first few cycles.
Recovery is rapid on drug withdrawal.
Oral contraceptives may affect migraine in the following
ways:
1. precipitation of attacks in the previously unaffected;
2. exacerbation of previously existing migraine;
3. alteration of the pattern of attacks – in particular, focal
neurological features may appear;
4. occasionally the incidence of attacks may decrease
or they may even be abolished while the patient is
on the pill.
Other important adverse effects include an increased incidence
of gallstones. There is a small increased risk of liver cancer.
There is a decreased incidence of benign breast lesions and
functional ovarian cysts. Diabetes mellitus may be precipitated
by the COC. Amenorrhoea after stopping combined oral
contraception is not unusual (about 5% of cases) but is rarely
prolonged, and although there may be temporary impairment
of fertility, permanent sterility is very uncommon.
Key points
Combined oral contraception (COC) – adverse effects
• thrombo-embolic disease;
• increased blood pressure;
• jaundice;
• migraine – precipitates attacks or aggravates previously
existing migraine;
• increased incidence of gallstones;
• associated with increased risk of liver cancer.
Risk–benefit profile
COCs cause no increased incidence of coronary artery disease,
but there is a two-fold increase in ischaemic stroke. The data
with regard to breast cancer suggest that there may be a small
increased risk, but this is reduced to zero ten years after stopping
the COC. With regards to cervical cancer, there is a small
increase after five years and a two-fold increase after ten
years of treatment. The risk of ovarian cancer and endometrial
cancer is halved and this benefit persists for ten years
or more.
Key point
The main mechanism of action of the combined oral
contraceptive is suppression of ovulation.
Contraindications of the COC
• Absolute contraindications: pregnancy, thrombo-embolism,
multiple risk factors for arterial disease, ischaemic heart