Benha University Hospital, Egypt ABOUBAKR ELNASHAR

In the 1960s the pill' was launched.

Thanks to Pincus & Rock

The most important method

Over 100 million women using oral contraceptives

world-wide

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Combined Oral Contraception

How does it work?

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Types

A. High estrogen dose

1. Anovlar 1

{EE 50 ug + Norethindrone acetate 1000 ug}

2. Primovlar

{EE 50 ug + Norgestrel 1500 ug}

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B. Low estrogen dose

It became popular during the 1970s in UK &

the 1980s in USA, but many of the original

studies were carried out before 1980.

a. Second generation:

Microvlar 30

{EE 30 ug + levonorgestrel 150 ug}

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b. Third generation:

Gynera & Minulet

{EE 30 ug + Gestodene 75 ug}

Marvelon

{EE 30 ug + Desogestrel 150 ug}

Cilest

{EE 35 ug + Norgestimate 250 ug}

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C. Multiphasic

Triovlar & Trinordiol:

6 pills {EE 30 ug + levonorgestrel 50 ug}

5 pills {EE 40 ug + levonorgestrel 150 ug}

10 pills {EE 30 ug + levonorgestrel 125 ug}

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Progestagen (ug) E.E (ug) Trade

name

Class

Norethisterone (1000)

Norgestrel (500)

50 Anovlar

Primovlar

High

Levonorgestrel (150)

Levonorgestrel (150)

Cyproterone acetate (2000)

Norgestimate (250)

Desogestrel (150)

Gestodene (75)

Drospirenone (3000)

35

30

Microvlar

Nordette

Dianette

Cilest

Marvelon

Gynera

Yasmine

Low

Norethisterone (1000) 20 Loestrine Lowest

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Steroid hormones

Estrogen

Mestranol

EE

Progestagen

Old: Norethisterone, Norethisterone

acetate, Ethindriol diacetate, Levonorgestrel

New: Norgestimate, Gestodene, Desogestrel.

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The current formulation

. decrease dose:

E: decrease 3 fold

P: decrease 10 fold

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. New P:

.Comparable with old P in regard to

BTB & amenorrhea.

.less androgenic,

.less adverse effects on lipid but

clinical significance is uncertain (Sperof,2002)

.Negligible impact on CHO

metabolism

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Drug Interactions With Oral Contraceptive Medications Whose

Action May

Cause Contraceptive

Failure

Medications Which

May Increase

OC Activity

Medications Whose

Clearance Can

Be Decreased by OCs

Carbamazepine Acetaminophen Amitriptyline

Griseofulvin Erythromycin Caffeine

Oxcarbazepine fluoxetine cyclosporine

Phenobarbitol fluconazole Diazepam

Phenytoin Fluvoxamine Imipramine

Primidone Grapefruit juice Phenytoin

Rifampin Nefazadone Selegiline

Ritonavir Vitamin C Theophylline

St. John’s Wort

Topiramate ABOUBAKR ELNASHAR

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Minor

N& V,

headache,

breast tenderness

25% discontinue

disappear immediately

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Unproven side effects

1. Melanoma

2. Hair loss

3. Cataract, intolerance to contact lenses

4. Agitation, Twitches

5. Joint pain

6. Respiratory infections, pneumonia

7. Mouth sores

8. Urinary tract problems

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Major

I. CVD,

II. Cancer

III. Liver disease

IV. Bowel disease

V. Reproduction

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I. CV risk

1. VTE

Relative risk of 3.2-4.1 of VTE compared with

non users.

The risk was unrelated to duration of use,

appeared within 4 months of starting the

COC & disappeared within 3 months of

stopping

(WHO, 1995).

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The risk was higher with COCs containing third

generation progestagens than with those containing

second -generation progestagens. The relative risks

were 2.6, 5.3 & 5.7 for COCs containing

levonorgestrel, desogestrel & gestodene,

respectively. Sperof (1996):

.Thrombosis is an E dose related complication & P

has no impact on clotting parameters

.Observational study, biased, prescribed to women

at high risk, numbers are relatively small ( 20-30)

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Some subsequent studies support these findings,

but others found no difference between COCs

containing second & third generation progestagens.

The absolute risk of women taking COCs containing

desogestrel or gestodene is very small & is much

less than the risk of VTE in pregnancy.

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VTE & factor V Leiden mutation.

Risk of VTE increases by 3to 4 x over the normal,

general incidence.

The minimal risk of venous thrombosis associated

with COCs does not justify the cost of routine

screening for deficiencies in coagulation system

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If a patient has a family history of idiopathic

thromboembolism or develops a thromboembolic

complication while taking COCs

(Vandenbruck,1994): 1. Antithrombin III deficiency: Antithrombin III.

2. Protein C deficiency: Protein C

3. Factor V Leiden mutation: Activated protein C

ratio

4. Protein S deficiency: Protein S

5. Prothrombin gene mutation: Activated partial

throboplastin time

6. Antiphosolipid syndrome:Anticardiolipin Ab,

Lupus anticoagulant Ab

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Other risk factors of CVD

Smoking, Increased age, hypertension, DM,

hyperlipaedemia.

No smoking: No increase risk of MI or stroke. No

increase death from CVD

< 15 cigarette/D: 3 fold increase in risk

>15 cigarette/D: 21 fold increase in risk.

OCP is safe , smoking is dangerous

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2. Myocardial infarction & stroke:

Low-dose COCs do not increase the risk of MI or

stroke in healthy nonsmokers, regardless of age (Sperof,2002).

No difference between 2nd & 3rd generation

products.

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3. Hypertension

Low dose COCs cause a rise of about 1.0 mmHg in

diastolic pressure, but this is clinically unimportant (Shen et al, 1994).

The benefits of COCs outweigh the risks for a

women with mild hypertension ( Diastolic BP <100

mmHg) (Grade A)

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II. Cancer risk 1. Hepatic adenoma: increase. Risk is related to duration & dose of pill. It may

regress with stop of pill. This is exceedingly rare in low dose

pills.

Hepatic carcinoma: no increase (WHO)

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2. Cancer cervix:

Incidence increased from 0.9 per 1000 women-

years with 2 years to 2.2 per 1000 women-years

after 8 yr (Oxford Family planing Association Study).

COC increases the risk of cervical adenocarcinoma.

The relative risk was 4.4 for >12 yrs of use (Ursin et al,1994)

Pap smear is recommended

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3. Breast cancer:

Royal College study: No increase .

L.Angeles Study: increase: > 5 yr., <25 yr., < first full-term pregnancy.

In 1996, a reanalysis of 54 studies: During COCs use & for 10 years afterwards there

is a small increase. , the relative risk is 1.24 in

users & 1.07, 5-9 years after stopping.

The dose & type of hormone had little effect.

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With the long latent period of breast cancer, this

study reflects the high dose era. There is evidence

that low dose COCs stimulate the breast less than

high -dose formulations

(Anderson et al,1989).

The effects of currently used COCs may be less than

those in this analysis & further studies are required.

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4. Choriocarcinoma:

No increase

5. Malignant melanoma:

No increase

.

6. Prolactin-secreting adenoma:

No relationship. No reported cases of tumor growth.

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III. Liver disease

No association with gall bladder disease

(Oxford FPA study).

COCs may accelerate existing disease

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IV. Bowel disease

COCs increase the risk of both ulcerative coloitis

(relative risk 2.0)& Crohn s disease (relative risk 2.6)

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V. Effect on reproduction

1. Inadvertent use during pregnancy:

No increased risk of teraratogenesis

2. Reproduction after discontinuing COCs

A. Delay of fertility for 2 months on average.

B. No increase in spontaneous abortion.

3. Diminished quantity & quality of breast milk, but no

impairment of growth

4. Post pill amenorhea:

No evidence of cause & effect

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.Largely ignored,

.Not dose dependent.

.They are attributed to suppression of ovulation.

.Women using low-dose COCs & women having

normal ovarian cycles are exposed to similar amounts

of E & P.

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Benefits of Pill: risk reduction in %

(Drife,2000)

90%: Ectopic pregnancy

80%: Luteal ovarian cyst

50% :PID, Menorrhagia, Iron deficiency anaemia,

Follicular ovarian cysts

40%: Dysmenorrhea, Cancer ovary, Cancer

endometrium, Benign breast disease

20%: Solid ovarian tumors

15%: Fibroids (after 5 yr)

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I. High efficacy

II. Protection against life threating diseases:

Ovarian carcinoma,

Endometrial carcinoma,

Colorectal cancer

PID,

Ectopic

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III. Decrease incidence of conditions that impair

quality of life:

menorhagia, dysmenorhea, functioning ovarian cyst,

benign breast disease

IV. Decrease incidence of:

Fibroid, endometriosis, toxic shock syndrome

V. Decrease incidence of :

Osteoporosis, rheumatic arthritis, thyroid disease,

peptic ulcer

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I. Well documented evidence:

1. Protection against life threating diseases: Ovarian carcinoma, Endometrial carcinoma,, PID, Ectopic

2. Decrease incidence of conditions that impair

quality of life: menorhagia, dysmenorhea,, benign breast disease,

functional ovarian cysts, endometriosis, acne, hirsutism

II. Growing evidence Decrease incidence of: Colorectal cancer, Osteoporosis

III. Limited evidence Decrease incidence of: Fibroid,, toxic shock syndrome

, rheumatoid arthritis

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I. High efficiency The most important health benefit of COCs is

effective prevention of pregnancy.

100% effective. Even where maternal mortality is

low, it is safer for a young woman to be on the pill

than to become pregnant

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II. Protection against life threatening disease

1. Ovarian cancer: 40%

Use for as little as 6mo.

The longer duration, the greater is the protection.

Protection persists after stop.

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2. Endometrial carcinoma:

Use for 1 yr.: decrease risk 50%.

The longer duration, the greater is the protection.

Protection persists after stop.

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Net effect of Ocs on the risk of cancer

(Schlesseman,1995)

For every 100,000 women from age 20-54 years

Non users Users for 8 years

Breast 2782 +151

Cervix 425 +125

Liver 20 +41

+ 277

Endometrium 438 -197

Ovary 369 -193

- 290

The net effect is negliable ABOUBAKR ELNASHAR

3. PID: 50%

It does protect against bacterial infection,

presumably because COCs thicken the cervical

mucous.

Decrease incidence & severity.

It protect against bacterial vaginosis & Trichomonas (Sperof,2002)

No effect on the risk of candidiasis or transmission

of viral agents such as herpes or HIV.

COCs increase incidence of cervical chlamydial

infection (cervical ectopy)

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4. Ectopic pregnancy:

90%reduction

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III. Decrease incidence of conditions that

impair quality of life?

1. Menorrhagia:50% decrease

2. Iron deficiency anemia.

3. Primary dysmenorhea

4. Premenstrual tension syndrome.

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5. Functioning ovarian cysts:

Follicular cyst (50%) & corpus luteum cyst (80%).

6. Benign breast disease (fibrocystic disease &

fibroadenoma):

After 2-4yr.

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IV. Decrease incidence of

1. Uterine fibroid:

Low dose OCP: no association (Oxford study).

OCP for 5yr.: decrease risk by 17%.

OCP for 10 yr.: decrease risk by 30% (Sperof,2002),

suggesting that the amount of estrogenic stimulation

provided by COC is less than during the normal

menstrual cycle.

2. Endometriosis

3. Toxic shock syndrome.

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V. Decrease incidence of

1. Osteoporosis:

controversial. Recent study: prolonged use:

powerful protection.

2. Rheumatoid arthritis:

Decrease 50% (R. College study). Protection disappears when they are stopped.

Other studies: no effect.

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3. Thyroid disease: (R College study).

Euthyroid swelling, thyrotoxicosis. Protection

disappears when pills discontinued

.

4. Peptic ulcer, earwax, acne.

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Non contraceptive uses of COCs

Menorhagia

Mysmenorhea

Functional ovarian cysts

Endometriosis

Acne

Hirsutism

PCOS

Premenstrual tension syndrome

Menstrual migraine

Diet or exercise induced amenorrhea.

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The WHO Guidelines (1996)

Category 1:

No risk. No restriction

Category 2:

Benefits > risks. Generally use the method

Category 3:

Risks > benefits. Relative contraindication

Category 4:

Unacceptable risk. Absolute contraindication.

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Category 4 = Absolute contraindication

1. History of or recurrent ischemic heart disease

2. History of stroke

3. History of or current DVT or pulmonary embolism

4.Vascular disease

5. Complicated valvular heart disease (pulmonary

hypertension, atrial fibrillation, history of subacute

bacterial endocarditis).

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6. Hypertension:

BP of 180/110 mmHg. BP of 160-179/100-109

mmHg warrants OC discontinuation in a current

user.

7. Smoking >20 cigarettes & age >35 yr

8. Major surgery with prolonged immobilization

9. Pregnancy

10. Breast feeding, <6 w postpartum

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11. Current breast cancer.

12. Benign or malignant liver tumors

13. Active viral hepatitis

14. Severe (decompensated) cirrhosis

15. Migraine headache with focal neurologic

symptoms.

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Category 3 = Relative contraindication

1. Hypertension

BP 160-179/100-109 mmHg

BP 140-159/90-99 plus other risk factors or no

monitoring

2. Smoking <20 cigarettes/d & age >35 yr

3. Diabetes with

retinopathy/nephropathy/neuropathy or with other

vascular disease or disease duration >20 yr

(Category 3/4 depending upon severity)

4. Genetic hyperlipidemias (category 2/3 depending

on type & severity)

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5. Postpartum <21 days

6. Breast feeding, 6 w to 6 mo (primarily breast

feeding)

7. Past breast cancer with no evidence for 5 yr

8. Unexplained suspicious vaginal bleeding (before

evaluation)

9. Mild liver cirrhosis

10. Long term use of enzyme inducing antibiotics or

anticonvulsants

11. History of OC-related cholestasis

12. Symptomatic biliary tract disease

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Category 2 = Generally can be used

1. Superficial thrombophlebitis

2. Thalssemias

(COCs may induce metabolic disorders)

3. Undiagnosed breast mass.

4. Major surgery without prolonged immobilization

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Category= Not a contraindications

1. Sickle cell disease:

androgenic P is beneficial. The risk of thrombosis is

theoretic (Sperof,2002) 2. Hypertension:well controlled patients

<35 & healthy (Sperof,2002)

3. Varicose veins.

4. > 35 yr.

5. Minor surgery.

6. Obesity

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.

7. Benign ovarian tumors

8. Benign breast mass

9. Family history of breast cancer

10. History of cholicystitis, PET, gestational DM, ectopic

pregnancy, Trophoblastic disease.

11. Viral hepatitis carrier

12. Thyroid disease:

simple goiter, hyperthyroid, hypothyroid

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.

13. Nulliparity

14. Tuberculosis.

15. Epilepsy:

COCs do not exacerbate epilepsy, but antiepileptic

drugs may decrease the effectiveness of COCs

no change or improvement.

16. Uterine fibroid:

low dose pills does not cause growth of fibroid &

bleeding decreases.

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In healthy females: the non-

contraceptive benefits outweigh the

risks.

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