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Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

BMJ 2011; 343 doi: (Published 25 October 2011) Cite this as: BMJ 2011;343:d6423

Rapid Response:

Changing doses and types of progestogens can increase mental illnesses and arterial effects

Why were most women in Professor Lidegaard's Danish study using
combined oral contraceptives containing desogestrel, gestodene,
drospirenone, or cyproterone which each increased risk of venous
thromboembolism by 6-7 times compared with non-current use?1 Is it
because women usually feel better if they use more oestrogenic

In Denmark 91.4% of 3 049 560 recorded women years of current use
between 1991 and 2009 was with COCs containing desogestrel, gestodene,
drospirenone, or cyproterone. Only 8.6% of current use was with
levonorgestrel containing COCs which had a 3 fold increased risk of venous
thromboembolism. Levonorgestrel has extra androgenic activity but no
inherent oestrogenic activity.

Lidegaard and colleagues believe that venous thromboembolism is the
greatest health risk for current users but this is not necessarily true.

Levonorgestrel is the active half of norgestrel which was tested,
along with other progestogens, in a range of doses in the 1960s in London.
John Pryse-Davies and I discovered that strongly progestogenic/low dose
oestrogen COCs increased monoamine oxidase activities throughout use and
were more likely to cause depression and loss of libido than more
oestrogenic COCs.2

Violence, like in an extended premenstrual syndrome, was noticeable
in such combinations when there were also marked arteriolar and venous
changes in the endometrium. Venous effects were commonest with more
oestrogenic COCs and increased with longer use. All cases of VTE or
thrombophlebitis were reported after the first 12 months of use.3
Lidegaard has recorded similar increased risks of VTE with both short and
longer use of the more oestrogenic progestogens.

Common reasons for early discontinuations or for women reqesting
different hormonal contraceptives are irregular bleeding, migraine
headaches, rapid weight gain or depressive mood changes.4

Violence was the commonest cause of death in current users the RCGP
pill study was from 1968 to 1972 when most current pill taking happened.
(The average use was recorded as only 44 months by 2010). There were 13
deaths from suicides accidents and violence compared with 6 in controls
and 7 deaths from arterial vascular diseases but only 2 deaths from venous
thromboembolism.5 By 2010 there were 156 deaths from violence in ever
takers of the pill compared with 51 in never pill users - adjusted
relative risk 1.92 (1.22 to 3.01).6

Such extended studies of pill ever users are usually confounded by
older age use of fertility drugs or HRT which prevent realistic and
accurate risk estimates. However in the RCGP study by 2010 the commonest
causes of death in ever users were cancers (1312), especially breast
cancer, and cardiovascular (353) and cerebrovascular (227) diseases.
Venous thromboembolism was not listed separately but presumably as a part
of other circulatory disease (126).

Thromboembolism is dramatic and life threatening but changing
progestogens types or using long-acting progestogen-only contraceptives
can also increase a range of serious health risks. Further details of
biochemical changes are freely available at

Very important increases in cancers and arterial and mental side
effects have been underestimated or ignored for 50 years to the detriment
of family health, presumably due to the overwhelming need for

1 Lidegaard O, Nielsen LH, Skovlund CV, Skjeldestad FE, Lokkegaard
E. Risk of venous thromboembolism from use of oral contraceptives
containing different progestogens and oestrogen doses: Danish cohort study
2001-9. BMJ 2011; (

2 Grant EC, Pryse-Davies J. Effect of oral contraceptives on
depressive mood changes and on endometrial monoamine oxidase and
phosphatases. BMJ 1968 Sep 28;3(5621):777-80.

3 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;4:73-7.

4 Anon Editorial. Changing oral contraceptives. BMJ 1969;4:789-791.

5 Royal College of General Practitioners. Oral contraceptives and
health. Pitman Medical, 1974

6 Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee
AJ. Mortality among contraceptive pill users: cohort evidence from Royal
College of General Practitioners' oral contraception study. BMJ

Competing interests: No competing interests

02 November 2011
Ellen C. Grant
Physician and medical gynaecologist - retired
Kingston-upon-Thames, KT2 7JU