THE ROLE OF ESTROGEN FREE PILL IN CONTRACEPTIVE CHOICE IS THIS THE WAY TO GO?

DR. PREMITHA

DAMODARAN

Choice Not Chance

Making Every Child a Wanted Child

Usage rates of different contraceptives across Asia-Pacific countries

Contraceptive Prevalence Rate (%)
China* 2
Korea* 2 Thailand* Vietnam* Australia India*
3 10 5 1 24 38 31 37 40

40 16
28

4 11 17 10

13 8 21 15 11 1

111

Pill Sterilization (Female & Male) Injectibles/ Implants IUDs

44
30

2 5 7 25

Condoms

Malaysia 0

13

4 5

MAPs/ Vaginal Barriers/ Female Condoms 60 80 100

20

40

Note : CPR includes the use of modern contraceptives such as pill, MAPs, Condom, IUDs, implants, etc and traditional methods such as rhythm, withdrawal, etc.

HORMONAL CONTRACEPTIVE USE IN MALAYSIA

Hormonal contraception usage is low (approx. 13%)
Source : IMS data 2010

COMBINED VERSUS PROGESTOGEN-ONLY PILLS

Combined Pills (E + P)
Cyclical pill-taking Regular bleeding cycle Contraindicated in some women Highly effective Causes anovulation Should not be used < 6 months lactation Some cycle-dependent complaints Estrogen-dependent symptoms can occur

Progestogen-only Pills
Continuous pill-taking Unpredictable bleeding **** POP safe in majority of women Less effective in non-lactating women **** About 50% cycles anovulatory **** Can be used only during lactation ****

May reduce cycle-dependent symptoms No estrogen-dependent side-effects

REDUCTION IN SYNTHETIC ESTROGEN DOSE

FDA approval of ENOVID

Norethynodrel 10 mg + mestranol 150 mcg

German approval of Anovlar

Norethisterone 4 mg + ethinylestradiol 50 mcg

EMEA approval of Minesse

Gestodene 0.06 mg + ethinylestradiol 15 mcg

1960 1961

2000

ESTROGEN DOSE AND VENOUS THROMBOEMBOLISM

Estrogen (ethinylestradiol) dose 3040 mcg

50 mcg

Odds ratio (95% CI)

1 (reference) 1.6 (0.92.8) 0.6 (0.40.9)*

20 mcg

*P=0.02
Lidegaard O, et al. Contraception. 2002;65:18796.

TYPES OF PROGESTOGENS

Progestogen
Progesterone Norethisterone (NET)1 Medroxyprog (MPA)1 Levonorgestrel (LNG)2

Progestational activity
1 4 4 6

Androgenic activity
+ + ++

Desogestrel (DSG)3

METABOLIC EFFECTS OF ORAL PROGESTOGENS

Negligible effect on haemostasis Negligible effect on lipid metabolism Negligible effect on carbohydrate metabolism No increased risk of MI, CVA or VTE
EJCRHC 1999

No effect on Blood Pressure

Spellacy & Birk 1974, Lawson 1992, Wilson et al 1984

CANCER EFFECTS OF ORAL PROGESTOGENS

Breast RR 1.17 for both POP and injectables (limited data)

1996 Lancet meta-analysis

Other cancers No increased risk for ovarian and cervical cancer,

RR 0.21 for endometrial cancer

1991 WHO Collaborative Study of Neoplasia and Steroid Contraceptives for injectables

ABSOLUTE CONTRAINDICATIONS TO PROGESTOGEN-ONLY PILLS

Past severe arterial disease or current arterial disease Porphyria Undiagnosed genital tract bleeding Pregnancy Sex steroid related cancers Decompensating / malignant liver disease

World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 4th ed. 2010.

PERCEPTION OF TRADITIONAL POPS

Traditional Progestin Only Pills 30 mcg levonorgestrel 350 mcg norethisterone 500 mcg ethynodiol diacetate

Seen as less effective/less popular than COCs Short safety window of 3 hours

Unpredictable bleeding pattern (29%) 47% discontinuation rate due to BTB

DESOGESTREL, ESTROGEN-FREE PILL

Contains 75 g desogestrel metabolised to etonogestrel has specific affinity to only progesterone receptor maximum serum levels within 2 hours

half life approximately 30 hours

excreted in urine and bile efficacy may be affected by liver enzyme inducing agents

DESOGESTREL, ESTROGEN-FREE PILL

Mechanism of Action
Ovulation inhibition by 97-99%

Pronounced reduction of LH
Thickens cervical mucus Tubal motility

Causes an inactive endometrium

Continuous daily regimen

no pill-free interval

OVULATION

Defined as follicular rupture followed by a rise in serum progesterone to > 30nmol/l

FOLLICULAR SIZE & SERUM PROGESTERONE LEVELS

DSG N=59 Foll rupture + prog > 30 nmol Foll rupture + prog 10-30 nmol Foll rupture + prog < 10 nmol 3%

LNG N=57 39%

0%

11%

97%

50%

Rice at al Human Repro 1999; 14: 982

CONTRACEPTIVE EFFICACY

Treatment

Women Years 727

Pregnancies

Pearl Index 0.14

75ug DSG

30 ug LNG

257

1.17

* including one ectopic pregnancy in LNG POP group, none with Cerazette
Collaborative Study Group. Eur J Contracept Reprod Health Care 1998

RISK OF ECTOPIC PREGNANCY

Levonorgestrel 1 ectopic in 250 woman years use Norethisterone 1 ectopic in 290 woman years use
Liukko et al 1977

No ectopic pregnancies in both the DSG group vs LNG group

Collaborative Study Group EJCRHC 1998

The 12 hour safety window with 75 ugm DSG

103 women aged 19-40 years with confirmed ovulation
Incidence of ovulation investigated over two cycles
3 tablets were taken 36 hours after the previous one (12 hours late) Incidence of ovulation and time required for ovulation to return after taking the last tablet was calculated

Results
One of 103 women ovulated twice during the study with no relationship to missed pills Minimum time to first ovulation was 7 days 17.2 days on average
Korver et al. Contraception 2005

VAGINAL BLEEDING PATTERNS

(90 DAY PATTERNS)

Definitions (Current WHO Criteria) Amenorrhoea Infrequent B/S Normal Frequent B/S Prolonged B/S no bleeding 1 or 2 B/S* episodes 3-5 B/S episodes 6 or more B/S episodes B/S episode > 14 days
* B/S = bleeding/spotting
Belsey EM, et al. Contraception 1986;34:253-60.

75 ugm DSG - BLEEDING PATTERN

More variable bleeding pattern than LNG Less bleeding / spotting with time

More Amenorrhoea
More infrequent bleeding

58% of women are willing to accept initial irregular bleeding if it results in fewer or no periods over time3

COC = combined oral contraceptive.

1. Ahrendt HJ et al. Eur J Contracept Reprod Health Care. 2007;12:354-361. 2. Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill. Eur J Contracept Reprod Health Care. 1998;3:169-178. 3. Hooper DJ. Clin Drug Investig. 2010;30:749-763.

Lactation / Breast Feeding with POP

75ugms DSG
has no influence on quality and quantity of breast-milk has no effect on growth rates of infants (2.5 years follow up) No change in duration of lactation No change in volume of Milk No change in composition of Milk

Bjarnadottir et al BJOG 2001

Change in Estrogen Dependant Symptoms after 3 Months of DSG

Ahrendt et al. Eur J Contracept Reprod Health Care 2007

Severe Dysmenorrhoea Before and After 3 Months of 75 ugms DSG

Dysmenorrhoea resolved/considerably improved in 93% * Analgesia use fell from 70% to 8%

Ahrendt at al. Eur J Contracept Reprod Health Care 2007

Mean Body Weight

starters/switchers
70 60 50
62.3 62.9 62.3 63.0

breast-feeding women
63.7 63.3 65.7 63.9

40
30 20 10 0 75 ugms DSG Pre-treatment 30 g LNG 1 year 75 ugm DSG 30 g LNG

Collaborative Study Group. Eur J Contracept Reprod Health Care 1998

WORLD HEALTH ORGANIZATION (WHO) GUIDELINES FOR CONTRACEPTIVE USE ELIGIBILITY

Class 1: A condition for which there is no restriction for the use of the contraceptive method Class 2: A condition in which the advantages of using the method generally outweigh the theoretical or proven risks Class 3: A condition in which the theoretical or proven risks usually outweigh the advantages of using the method Class 4: A condition that represents an unacceptable health risk if the contraceptive method is used
World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 4th ed. 2010.

WHO MEDICAL ELIGIBILITY CRITERIA COC VS POP

Patient Subset
Smokers aged 35 years, > 15 cigarettes per day Smokers aged 35 years, <15 cigarettes per day Smokers aged <35 years Controlled hypertension SBP 140-159 or DBP 90-99 History of hypertension in pregnancy Migraine no aura, aged 35 years Migraine no aura, aged <35 years Breastfeeding 6 weeks to 6 months postpartum Breastfeeding >6 months postpartum Obese women (Body Mass Index 30 kg/m2)

COC
4 3 2 3 3 2 3 2 3 2 2

POP
1 1 1 1 1 1 1 1 1 1 1

Women aged 40 years

COC = combined oral contrceptive; POP = progestin only pill. World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 4th ed. 2010.

75 ugms DESOGESTREL

COMBINED VERSUS PROGESTOGEN-ONLY PILLS

Combined Pills (E + P)
Cyclical pill-taking Regular bleeding cycle Contraindicated in some women

Cerazette
Continuous pill-taking, 12 hour window More amenorrhoea, less spotting with time Safe in majority of women

Causes anovulation
Should not be used < 6 months lactation Some cycle-dependent complaints Estrogen-dependent symptoms can occur

About 97% cycles anovulatory

Can be used anytime May reduce cycle-dependent symptoms No estrogen-dependent side-effects

Other Effects of Cerazette

Negligible effect on haemostasis No increased incidence of VTE Negligible effect on lipid metabolism Little affect on adrenal or thyroid function

Negligible disturbance carbohydrate metabolism

No effect of lactation and growth of newborn

Other Effects of Cerazette

Treating cycle-related symptoms
Premenstrual symptoms
Dysmenorrhoea/pelvic pain associated with endometriosis 50% reduction after 6 months in patients with mild endometriosis (P<0.001)

Migraine headaches

reduction in frequency (P<0.001) after 4 months of use

68% reported 50% reduction in migraine intensity and/or duration
Georgantopoulou CJ Pediatr Adolesc Gynecol.2009; Razzi et al. Eur J Obstet Gynecol Reprod Biol.2007; Nappi et al. Contraception 2011; Ahrendt HJ. Curr Med Res Opin. 2010

Using Cerazette

COC, rings, patches, POPs

Immediate change, start on day 1 of cycle No additional contraceptive cover needed

Lactation
Day 21 and no additional cover needed

Post-abortion
Immediately and no additional cover needed

Outside of this time

Ensure that the woman is not pregnant Needs to use condoms/abstain for 7 days

Using Cerazette / POP (Missed Doses)

CERAZETTE

An Estrogen Free Contraceptive A Good Alternative