University of Warwick MSc course 2007

Combined hormonal

contraception

Types

• Oral (COC pill)

• Transdermal

• Vaginal ring

• Injectable

History of COC

• 1950 Synthesis of norethisterone

• 1956 First human trials reported

• 1961 COC available in UK

• 1963 Synthesis of norgestrel

Composition of COCs

• Ethinylestradiol 20 – 35 mcg

• Progestogen

Constituents of COCs

• Oestrogens

• Ethinylestradiol• Mestranol

• Progestogens

• Norethisterone• Levonorgestrel• Norgestimate• Desogestrel• Gestodene• Drosperinone

Formulations

• Monophasic

• Phasic (biphasic, triphasic)

• Everyday (ED)

• Seasonale (four packets in a row)

• Lybrel (continuous)

ONS Omnibus Survey

Pill use by age GB 2004/5

0

10

20

30

40

50

60

16-17 18-19 20-24 25-29 30-34 35-39 40-44 45-49

%

Trussell 2004

Failure ( first year unintended pregnancy % rates)

Method Typical use Perfect use

COC/POP 8 0.3

Evra 8 0.3

NuvaRing 8 0.3

Lunelle 3 0.05

Mechanism of action

• Inhibition of ovulation through suppression of the hypothalamic-pituitary-ovarian axis

• Endometrial suppression

• Thickening of cervical mucus

Non-contraceptive benefits

• Better cycles: lighter & shorter (less anaemia), regular, less dysmen, less PMS

• Less PID• Fewer ectopics• Less benign breast

disease• Bone sparing

• Fewer functional ovarian cysts

• Less hospitalisation for fibroids

• Less symptomatic endometriosis

• Protection against carcinoma of ovary, endometrium and colon

Risks/benefits

• Risks apply to a minority

• Benefits apply to all

What women worry about

• Infertility

• Cancer

Expressing risk

• Relative risk can be misleading and anxiety provoking for women

• Use absolute risk

Annual deaths per million

0

20

0

40

0

60

0

80

0

10

00

12

00

14

00

16

00

18

00

Childbirth, UK

VTE M30

VTE off COC

COC all causes

Home accidents

RTAs

Scuba diving

Smoking (in next year age 35)

Risks of VTE per 100,000 per year

0 10 20 30 40 50 60 70

Pregnancy

Gestodene/desogestrelCOC

LNG/NE COC

No COC

Co-cyprindiol (Dianette)

• 35mcg EE with 2mg cyproterone acetate

• not licensed as a contraceptive

• indicated for severe acne which has not responded to antibiotics

• RR of VTE compared to LNG COCs is 3.9

Body mass index and COC

• Traditionally, BMI 30-39 regarded as relative contraindication and 40+ absolute contraindication

• WHO-MEC gives a BMI of 30 and over a category 2 (advantages generally outweigh risks), with no upper limit

Risk factors for arterial disease

• Smoking, esp. > 15 cigs/day• Hypertension• Diabetes• Android obesity• FH arterial/venous thrombosis• Age• Hyperlipidaemia• Migraine

Risk factors for VTE

• FH of VTE/genetic predisposition• Acquired e.g. antiphospholipid (Hughes’)

syndrome• Obesity: BMI > 30• Severe varicose veins• Dehydration• Trauma and immobilisation• Age

Thrombophilias

• Factor V Leiden mutation• G20120A mutation• Protein C deficiency• Protein S deficiency• Antithrombin III deficiency

Prevalence of factor V Leiden mutation is 1 in 20; if these individuals take a COC, risk of VTE is increased 35-fold or absolute risk 3 additional cases of VTE per 1000 users per year.

Ischaemic stroke

• Risk of ischaemic stroke for COC users: OR 2.7 (2 meta-analyses with combined total of studies of 28)

• Among women who do not smoke, have no history of migraine, have regular BP checks and who are normotensive increased risk is less

Myocardial infarction

• Risk of MI for COC users: OR 2.0 for 30mcg pills and 0.9 for 20mcg pills (meta-analysis of 23 studies)

• In smokers on COC, OR 9.5 cf non-smokers not on COC

• Women who do not smoke, who have regular BP checks and who do not have hypertension or diabetes are at no increased risk of MI, regardless of their age

Breast cancer

Conflicting data from different studies• Collaborative reanalysis Lancet 1996: relative

risk for current users = 1.24• Marchbanks case-control study NEJM 2002

showed no increased risk in current users aged 35-64 at time of diagnosis

No duration of use effect and no synergy with FH of breast cancer

Cervical cancer

• Increased risk of cervical neoplasia (invasive/in-situ) with duration of COC use > 5 years; RR 2.2 with duration 10+ years (systematic review Lancet 2003)

• COC users can avoid this risk by attending regularly for cervical screening at usual intervals

Diabetes and COC

• WHO4 if:– retinopathy– nephropathy– neuropathy– duration of diabetes > 20 years

Contraindications

• Cardiovascular

• Hepatic

• Other

Cardiovascular disease

• Hypertension: > 160/100

• Ischaemic heart disease

• Stroke

• Valvular heart disease complicated by pulmonary hypertension, atrial fibrillation or infective endocarditis

Liver disease

• Viral hepatitis: active

• Cirrhosis

• Benign tumours (adenoma)

• Malignant tumours (hepatoma)

• Acute hepatic porphyrias

• Gallbladder disease: symptomatic or medically treated

Other contraindications

• Pregnancy

• Genital tract bleeding

• Oestrogen-dependent tumours

COC and migraine

The following are WHO4:• Loss of part of visual field• Unilateral weakness/parasthesiae• Speech disturbance• Status migrainosusThe following are safe: blurred vision,

photophobia, phonophobia and flashing lights affecting whole visual field

Starting routines

• WHO Selected Practice Recommendations: up to day 5 of cycle

• Quickstart: confirm not pregnant, then start any time with extra precautions for 7 days

Starting routines after pregnancy

• Start the day after the 2nd visit/expulsion for medical abortion or the day after a surgical procedure (earliest recorded ovulation day 16)

• Start in the 4th week after delivery (clotting factors still raised for up to 3 weeks; earliest recorded ovulation day 30)

FFP April 2005

Missed pills

• Definition now is 24 hrs late

• If 2 x 20mcg pills or 3 x 30mcg pills are missed:– take a pill a.s.a.p.– addit. precautions for next 7 days– ? EC if missed pills in week 1 – omit PFI if missed pills in week 3

Side effects: oestrogen excess

• nausea• dizziness• cyclical weight gain• bloating• vaginal discharge• breast tenderness

Change to 20mcg pill or to a more progestogenic pill e.g. Loestrin 30 or Norimin

Side effects: progestogen excess

• dry vagina• sustained weight gain (increased appetite)• depression• loss of sexual drive• lassitude• acne/hirsutismChange to more oestrogenic pill e.g.

Ovysmen/Brevinor or to a less progestogenic pill e.g. Femodene or Marvelon

Causes of BTB

• Cervical bleeding:– ectropion– cervicitis– carcinoma cx.

• Chlamydia• Pregnancy:

– miscarriage– trophoblastic disease

• Missed pills• Drug interaction• Vomiting• Severe diarrhoea• Vegetarian diet• Malabsorption e.g.

coeliac disease• Smoking

Enzyme-inducing drugs

• Antiepileptic drugs– carbamazepine– oxcarbazepine– phenytoin– phenobarbital– primidone– topiramate

• Herbal– Hypericum

• Anti-TB drugs– rifampicin– rifabutin

• Antifungal drugs– griseofulvin

• Antiretroviral drugs– see BNF

• CNS stimulants– modafinil

Broad-spectrum antibiotics

• May reduce efficacy of COCs• Impair bacterial flora responsible for

recycling of EE from large bowel• Flora develop antibiotic resistance after

3 weeks• Broad-spectrum penicillins e.g.

amoxicillin; cephalosporins; tetracyclines

Extended use

• Tricycling/continuous use

• Fewer withdrawal bleeds

• Ovulation better suppressed

• Fewer missed pills

• Treatment for dysmenorrhoea and menorrhagia

• Good for military

Evra 1

• A flesh-coloured combined transdermal patch

• ethinylestradiol 20µg/norelgestromin 150µg

• 4.5 x 4.5 cm• patches last 7 days• worn for 3 weeks out of four • Launched in UK in 2003

Evra 2

Compared to COC:• compliance better, especially in teenagers• efficacy as good as COC overall, but not so

good in those > 90kg• BTB more common in cycles 1 & 2• mastalgia more common in cycles 1&2• 3% discontinue because of skin reactions

Patch rules

• Patch detachment in last 24 hrs: no additional precautions needed

• Delayed patch application (patches 2 or 3): up to 48 hr window where no additional precautions needed

NuvaRing 1

• A combined vaginal ring• made of ethylene vinylacetate• ethinylestradiol 15µg/

etonogestrel 120µg• 5.4cm diameter• worn for 3 weeks out of 4• almost all have regular withdrawal

bleeds

NuvaRing 2

• Steady state release level within 3 days of insertion

• Efficacy similar to COC• Incidence of BTB low• Can cause vaginal discharge• Can be removed for 3 hours for sex• Tampon use is OK• Available in US, Canada, Australia and many

European countries including Ireland

Lunelle

• A combined monthly injectable• medroxyprogesterone acetate 25mg/

estradiol cypionate 5mg• similar efficacy to COC• most have regular withdrawal bleeds• <5% amenorrhoeic by one year• rapid return of fertility• not yet available in UK