A Textbook of Clinical Pharmacology and Therapeutics

FEMALEREPRODUCTIVEENDOCRINOLOGY 309

Key point

The main mechanism of action of the combined oral

contraceptive is suppression of ovulation.

release by the pituitary via negative feedback on the hypothal-
amus. This prevents the mid-cycle rise in LH which triggers
ovulation.
Progestogens currently used in combined oral contracep-
tives include desogestrel,gestodeneandnorgestimate. These
‘third-generation’ progestogens are only weak anti-oestrogens,
have less androgenic activity than their predecessors (norethis-
terone,levonorgestrelandethynodiol) and are associated with
less disturbance of lipoprotein metabolism. However, deso-
gestrelandgestadenehave 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 thyroid-
   binding 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 thrombo-
embolic 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 con-
tinuously. 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 contra-
ceptive, the incidence of VTE is about five cases per 100 000
women per year. For those using the COC containing a second-
generation 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
asdesogestrelandgestodene, 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 clin-
ically 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 low-
est 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 preg-

nancy 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 inci-

dence of gallstones. There is a small increased risk of liver can-

cer. There is a decreased incidence of benign breast lesions and

functional ovarian cysts. Diabetes mellitus may be precipi-

tated 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 stop-

ping 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 endome-

trial cancer is halved and this benefit persists for ten years

or more.

Contraindications of the COC

• Absolute contraindications: pregnancy, thrombo-embolism,
  multiple risk factors for arterial disease, ischaemic heart