Download Ethinyl-estradiol

Family Planning & Contraception
Manuela Russu MD, Ph D
Associate Professor
Chief of “Dr I. Cantacuzino”
Second Department
of Obstetrics & Gynecology
“Carol Davila” University of Medicine & Pharmacy
MCR, 2010
 Various surveys indicate that 30% to 60%
of conceptions worldwide are either
unwanted or unplanned
 Even in USA, many pregnancies occur
due to:
• ignorance,
• unavailability, or
• unacceptability of the rather limited range
of fertility-control methods presently in use
Harlap S, et al, 1999
When to recommend contraception
 Whenever pregnancy is not desired in sexual active
women
 From puberty to menopause: from menarche to 50’s
 At least some girls, & perhaps the majority, ovulate before
their first menstrual period
 Therefore, older women are probably best advised that
regular menstrual periods imply recurrent ovulation
irrespective of age. A woman younger < 50 yrs who has not
menstruated for 2 ys is very unlikely to ovulate spontaneously
and to conceive, although there are reported instances in
which conception occurred more than 2 ys after the onset of
documented hypergonadotropic, hypoestrogenic amenorrhea
Szlachter BN, Nachtigall LE, Epstein J, Young BK, 1979
Classification
Oral:
COC, POP

Injectables (long term)
12 ; 8; 4 weeks

Transdermal & intravaginal

Implants


Hormones:


IUD



Barriers
Female’s, male’s





Natural

(Periodic/Rhythmic abstinence)








Definitive sterilization
Inert
Medicated
Physical
Chemicals
Physic-chemical
Prolonged breast feeding
Interrupted intercourse
Calendar Rhythm Method
Temperature Rhythm Method
Cervical Mucus Rhythm Method
Symptothermal Method
Contraceptive Choice Factors
 Couple Factors: Motivation & Reliability
 Age
 Life-style
 Sexual frequency
 Family-size desires
 Previous contraceptive experience
 Feminine attitudes & Masculine attitudes
 Health Factors: Absolute or Relative Contraindications
 Health status
 History: menstrual, pregnancy, family
 Physical & Pelvic examination
 Contraceptive Method Factors: Acceptability and Continuing Use
 Effectiveness
 Minor side-effects
 Disadvantages
 Potential complications
 Cost
Pearl Index of Contraceptive Methods
Leidenberger EA, 1998
COC
0.03- 0.5
POP
0.4- 4.3
Injectables
0.03-0.9
Implants
0- 0.2
Condoms
7- 14
IUD copper
0.5-1.0
IUD with
Levonorgestrel
Progesterone
0.09- 0.2
No method
> 80
R. Pearl , 1932
No. of unwanted pregnancies/
100 yrs of use
Failure Rate
COC, POP, injectables
Depends of correct use:
[7’s Rule]
Diarrhea/ vommisments
Other medication
Contraceptive Effectiveness
Trussel J, Haycher RA, Cates W. Jr, 1990
Method Approximate Use Effectiveness (%)
Male sterilization
Female sterilization
Injectable progestin (Depo-Provera)
Implantable progestin capsules (Norplant)
Oral steroids: combination
IUD: copper
IUD: progesterone
Oral steroids, progestin only
Diaphragm & spermicide
Condom only
Sponge with spermicide
Spermicide only
Cervical cap
Periodic abstinence
Preejaculatory Withdrawal
99+
99+
99
99
98
98
96
95
90
88
88
85
80
75
70

No contraceptive method is fully
effective for preventing pregnancy, nor fully
safe from both minor and major side-effects,
nor fully acceptable to the couple

Since each method has its advantages
and disadvantages, the method that the couple
will use in a consistent manner is the “best”
contraceptive method for them
Counselling woman/man
• Advantages, disadvantages
• Indications, contraindications, side effects
For each method of contraception
Mechanism of Action of COC
Hypothalamus
GnRh Blockade
Pineal Gland
FSH & LH Blockade
Ovary
ER & PR Blockade,
Follicular maturation inhibition,
Techal & granulosa cells’development inhibition
Endometrium
Ovoimplantation Inhibition
Cervix
Mucus changes:
impairs sperm transport
Other beneficial effects of COCs (1)
↓ menstrual blood flow
 ↓ dysmenohrrea
↓ ovarian cysts incidence
↓ PID incidence
↓ endometrial & ovarian cancer risk
↓ benign breast diseases
↓ colon- rectal cancer risk
 prevention of atherogenesis
 improvement of rheumatoid arthritis
Other beneficial effects of COCs (2)
A. Therapeutic effects: healing/
alleviation of symptoms of some
diseases
B. Protective effects : reduction
of some diseases’ incidence
Other beneficial effects of COCs (3)
A. Therapeutic effects




Menstrual bleeding control:
Reducing dysfunctional uterine bleeding
(puberty, premenopause), by central- ovarian balance
and hormonal endometrial balance, in anovulation,
dysovulation and corpus luteum insufficiency
Reducing dysmenorrhea: hormonal balance
(progestogens act as antiprostaglandins)
Reducing the premenstrual syndrome in some
cases (±): see Yaz effects of reducing dysforia
Other beneficial effects of COCs (4)
A. Therapeutic effects



Decrease female androgenicity (because
testosterone excess or Androgen Receptors
excess): constitutional, tumors
Reducing hirsutism: blockade of pillar
follicles
Reducing ackne: decrease the sebum
secretion of sebaceous glands, disparition of
comedoms, pustules, skin abcesses and necrosis
Partial antiandrogenic effect of some progestogens
Other beneficial effects of COCs (6)
B. Protective Effects
 PID protection (Chlamidya trachomatis/ N.
gonorrhoea):↓ incidence, severity, sequels (infertility,
ectopic pregnancy, chronic abdominal pain)
 Protection of ectopic pregnancy
 Protection of myomas, endometriosis
 ↓ ovarian tumors incidence /PCO/ cancer (ovulation
blockade)
 ↓ endometrial cancer incidence (daily hormonal balance,
antiproliferative effect of progestogens)
 Protection of benign breast tumors
↓ breast hyperplasia
 Protects of colon- rectal cancer
Drugs Interactions

phenytoin, phenobarbital, primidone, diazepam, alprazolam
↑ liver metabolism

rifampin, penicillins, tetracycline/doxycicline,
griseofulvine
↓ absorbtion


folic acid, ascorbic acid, Zn, B2 vit, B12 vit
phenylbutazone
↓ contraceptive effect
Possible Adverse Events
I.


II.
(1)
Pregnancy like changes
↑T4, TBG, ↓ T3
↑ transcortin, cortisol
Metabolic changes
Lipoproteins: LDL/HDL:HDL 2, HDL3; but
COC are not atherogenic : Wallach M, Grimes DA, 2000

Carbohydrate: diabetes effect was real with higher
formulations; no concern with actual formulation:
Speroff L, Darney PD, 2001

Proteins:

↑ angiotensinogen: “pill- induced hypertension”

↑ fibrinogen; clotting factors: II,VII, IX, X, XII, XII:
direct connection to estrogen dose

Possible Adverse Events
III.
(2)
Cardiovascular effects
Vasoconstriction ↑, platelets aggregation ↑

deep vein thrombosis, pulmonary embolism
myocardial infarction () + ischemic & hemorrhagic
stroke
hypertension

IV. Liver Disease


cholestasis, cholestatic jaundice
gallbladder lithiasis
Possible Adverse Events
(3)
Cardiovascular effects
Venous Thrombosis & Embolism: Relative Risk
Thrombosis during pregnancy
Thrombosis on COC with E < 50 μg
6 /10,000
4 /10,000
Thrombosis on non- users
0.5-3/ 10,000
High Risk

Age > 35 yrs, diet, lifestyle, smoking, obesity, surgery

Predisposure at thrombofilias: protein C & S deficiency,
resistency at activated C protein/ factor V Leyden mutation,
antithrombine III deficiency, prothrombin mutation,
hyperhomocisteinemia, antiphospholipid antibodies syndrome
(anticardiolipinic, lupus anticoagulant)

Different diseases: DM, LES, hemolytic uremyc syndrome, Crohn D, sickle cell
anemia
Possible Adverse Events (4)
V.




Some neoplasias stimulation
Preinvasive and invasive Cervical Cancer after 5 yrs of use: HPV
Thomas DB, 1996
Breast Cancer (after 12 yrs of use): RR 1.24; lower stadies
 gradually after 10 yrs from interruption (because of progestogens): The
Collaborative Group on Hormonal Factors in Breast Cancer, 1996
Liver Nodular Hyperplasia & Cancer
Pineal Gland Adenomas (specially prolactinoma)
VI. Effects on reproduction



Postpill Amenorrhea: is likely reflective of preexisting problem
Wallach M, Grimes DA, 2000
Congenital Defects: no association: Lammer EJ , Cordero FJ, 1986
Lactation Decrease: actually ambiguous resultats: to be started
after 3 weeks postpartum: Kaunitz A, 1997
Adverse Events
(5)
Oxford Family Planning, 1995
Royal College of General Practitioners, 1999
A. general: commune (1)






Headache
Mastalgia; breast enlargement
Nausea
Nervousness
Irritability
Oedema/ Weight gain
Variable:
patient, formula
Diminish/ Increase with time
Possible Adverse Events
(6)
Oxford Family Planning, 1995
Royal College of General Practitioners, 1999
A. general : rare events (2)







Migraine headaches
Dizziness
Visual disturbances & eyes irritation (contact lens)
Libido changes
Different skin changes: hyperpigmentation/chloasma –
less with low dose of E, nodos erytema, hair loss
Mood changes: emotional lability, hyperreactvity/depression: reduced by low dose E
Vommisments
Possible Adverse Events
(7)
Oxford Family Planning, 1995
Royal College of General Practitioners, 1999
A. general : very rare events (3)






deep vein thrombosis & pulmonary embolism
arterial thrombosis [myocardial infarction () ,
ischemic & hemorrhagic stroke]
hypertension
coronary heart disease
liver adenomas
cholestasis jaundice
Possible Adverse Events
(8)
Effects on Reproduction
Amenorrhea:
Usually in cases on psihiatric therapy, which

influences hypothalamo- pituitary-ovarian axis together with COC
&

Interacts to mono-aminergic neurotransmitters metabolism
Conclusions :
If the patient on psyhotropic drugs has menstrual
irregularities the collaboration between gyncologist &
neuropsyhiatrist is mandatory
2. Any drug influencing hypothalamic system must
atentivelly follow –up in women on COC
1.
Possible Adverse Events
(9)
Effects on Reproduction
Ovulation recovery after COC
 First cycles after COC become biphasic, with some
prolongation of proliferative phase and menstrual delay
of 6-8 days
 After long term use of COCs amenorrhea may appear,
with high frecquence at adolescents and some delay in
ovulation recovery
 Short term COC administration may stimulate fertility
and if pregnancy is unwanted, is not recommended to
stop COC
Possible Adverse Events
(10)
Effects on Reproduction
Interference with Pregnancy
 Administration during pregnancy was considered an
absolute contraindication, because interferention with
organogenesis dependent on steroid hormones: external
genitalia, but a recent meta- analysis (Raman –Wilms L, et
al, 1995) did not confirm any congenital malformation
 For pregnancy safety is not imposed a longer break than 7
days (after the last pill from the blister)
 Usually COC are not recommanded during lactation:
because excretion in milk
COCs’Adverse Efecte : Breast Cancer
Magnusson CM, et al; Sweden (Int J Cancer, 1999)
Case- control population epidemiological study
based on phone administered questionnaires:
•
compairs 3016 women (50-74 yrs) with invasive
breast cancer to 3263 (same ages) as control group

No risk of breast cancer when on COC
This large population study brings evidences on
environment factors which act in the first years
after menarche and emphasizes the births’
importance at younger ages to prevent breast
cancer
Adverse Effects of COCs: Breast Cancer: Chie WC, et al :
•
•
•
National Taiwan University Hospital, Taipei (Int J Cancer, 1998)
During 16 months- in 1995- 1994:
174 new cases with breast cancer & 435 controls (same age, with
nonmalignant & nongynecological pathology)
Breast cancer: 25 studied (14.4%) and 47 controls (10.4%), of which 9
studied (5.2%) & 15 controls (3.3%) used COC > 5 years
COC/ without COC
OR
Confidence Interval
(95%)
COC
1.7
0.9- 3.2
Before 25 yrs
3.4
1.2- 9.7
Before 1971
3.2
1.2- 8.9
Premenopause before 25 yrs
5.8
1.5- 22.1
Premenopause > 5 yrs
3.5
0.9-14.3
Postmenopause < 1 yr
7.5
1.1-50.1
Breast cancer risk was moderate increased when using COC before 25 yrs,
before 1971 & > 5 yrs of use
Risk of death
Mortality associated to COC use is very low if:
• woman is younger than 35 yrs,
• has no systemic illness
• does not smoke
1 death/ 55,000 woman-years
from the Group Health Cooperative of Puget Sound:
Porter JB, et all, 1987
Contraindications of COC
Physicians Desk Refference, 2004
 Thromboflebitis & thromboembolic disorders: history/current
 Cerebrovascular or coronary artery disease
 Thrombogenic heart valvulopathies
 Thrombogenic heart arrhythmias
 Diabetes mellitus with vascular involment
 Uncontrolled hypertension
 Known or suspected breast carcionoma
 Carcinoma of endometrium or other known or suspected estrogen
dependent neoplasia
 Undiagnosed abnormal uterine bleeding
 Cholestasis jaundice of pregnancy or jaundice on pills use
 Hepatic adenomas/carcinomas or active liver disease as long as liver
function has not returned to normal
 Known or suspected pregnancy
Warnings for COC
Physicians Desk Refference, 2004
 Cigarette smoking increases the risk of serious
cardiovascular side effects from COC.
 This risk increases with age and with extent of
smoking (in epidemiological studies: smoking 15 or
more cigarettes per day was associated with a
significantly increased risk) and is quite marked in
women older than 35 yrs of age
 Women on COC should be strongly advised not to
smoke
History of progestogen use
1934
Replacement for ooforectomysed women
(Kaufmann)
1937
Oligo- & hypermenorrhea treatment (von Kehrer)
1938
Anovulation treatment (Glauberg)
1953
Abnormal uterine bleeding treatment (Kaufmann)
Contraception with cu norethinodrel,
norethisterone (Gregory Pincus, USA)
Endometriosis treatment (Kistner)
1954
1960
‘70
HRT in postmenopause
Hormonal Contraception (1)
Estrone, Estradiol,
Estriol
Natural Sexual
Steroids with
proliferative effects
Ethinylestradiol
Synthetic Steroid
inducing comparative
effects of natural
ones, using the same
receptors
Hormonal Contraception
Ethinyl-estradiol:
Orally

(2)

0.050 mg
0.030 mg/0.035 mg
0.020 mg
0.015 mg

0.020 mg

1mg;2mg; 3mg



Transdermal 
{Mestranol: not in use}
Estradiol valerate
Orally
Hormonal Contraception (3)
Progesterone
Hormone which
maintains the
pregnancy
Progestogens
Steroids inducing
secretory effects on
endometrium
previously estrogen
stimulated
Hystory of use of estrogens and
progestogens in contraception
1938: Ethinyl-estradiol introduced in contraception: oral/ transdermal
2000: Estradiol valerate: introduced in contraception: oral
B.
A. Oral progestogens
1.
2.
3.
4.
5.
Injectable progestogens
Medroxy- progesterone: DMPA *
Norethisterone: Noristerat*
C. Transdermal Progestogens :
Norelgestromin : Ortho
Evra/Evra*
Norethisterone
Levonorgestrel
Cyproterone acetate
Desogestrel, gestodene, norgestimate
Dienogest: summarises the effects of 19-
norproprogestogens and of progesterone derivates, without
their negative effects
6.
Drospirenone
Progestins’ Classification
Progestins
Pregnans
Norsteroids
Estrans
Norpregnans
Nomegestrol
Gonans
Norethisterone
Nestoron
Etinodiol
MPA
Levonorgestrel
Linestrenol
Norgestimate
Dienogest
Desogestrel
Gestoden
Clormadinon
Cyproteron
Trimegestron
Spironolacton
Drospirenone
Differences between COC (1)




Biodisponibility
Progestative Power
Uterotropic Index  menstrual cycle
control + dysmenorrhea control
Metabolic effects
Comparation of different types of
progestogens
Androgenic
activity
Antiandrogenic
activity
Antimineralcorticoid
activity
Glucorticoid
activity
Drospirenone
-
(+)
+
+
+
-
Cyproterone
acetate
-
+
-
(+)
3 ketodesogestrel
(+)
-
-
-
Dienogest
Gestoden
(+)
+
-
(+)
-
Levonorgestrel
(+)
Norgestimate
(+)
-
-
-
Progesterone
Legende: + action; (+) negligible action at therapeutical dose; - without action
Differences between COC (2)


-
COC Structure differs the old formulation from the new ones,
in which estrogen & progestogen doses are less, with wish to
reduce adverse events.
There are limits to which compounds doses can be reduced:
Maintenance of contraceptive efficacy with an satisfactory
Pearl index
This necessity can be obtain on pills with
small doses in a regimen of 24 days:
example: 15 µg ethinyl estradiol + 60 µg gestoden
Brincat M, Muscat Baron Y, Galea R, 2003
Criteria in choosing a
contraceptive pill



Good control of menstrual cycle
Low dose of estrogens
High tolerance
Types of COCs
(with 21, 24 or 28 tb/cycle: 21+ 7 inert; 26 +2 inert)

Mono-phasic

Bi-phasic

E/P:21
e/p: 11
Tri-phasic
e/p:6


e/P:10
Four-phasic
Normophasic
(secquential)
e/P: 10
E/P:5
E
P
A Novel four phasic COC
An investigational, four-phasic oral contraceptive (OC) containing
natural estradiol (E2) valerate + dienogest, a progesterone formulation
commonly used in Europe but not in the United States, "is expected to
become the first globally available E2-containing OC”American College of Obstetricians and Gynecologists 56th Annual


•
•
•
•
•
Clinical Meeting- 8 May 2008
Women received 20 cycles of 28 days of the four-phasic OC.
Each cycle contained:
2 days: E2 valerate 3 mg,
5 days: E2 valerate 2 mg/dienogest 2 mg,
17 days: E2 valerate 2 mg/dienogest 3 mg, and
2 days: E2 valerate 1 mg, and
2 days: placebo.
New revolution in contraception
Quilara the four phasic contraceptive :
 55 th Annual Meeting of ACOG (San-Diego, May
2007)
 Congress of Contraception and Health
Reproduction Care (Praga, May 2008)
 World Congress of Controversis in Obst- Gynecol &
Infertility (Paris, Nov. 2008)
 Congress of the European Society of Gynecology
(Rome, Sept. 2009)
Novel approaches to avoid
bleeding (1)
Loudon NB,1977: tried the approach that
gained interest around the year 2000 when
surveys of women's attitudes toward monthly
menstrual bleeding started to show a major
change:
 more and more women declared that they
would welcome a hormonal contraceptive
method that reduced bleeding episodes to
4, 2 or even 1 per year.
Novel approaches to avoid bleeding (2)
 The first new modality consisted of changing the 7 day
medication-free interval, either shortening it to fewer
than 7 days, or by the administration of low-dose
estrogens during the interval between packages.
continuous administration regimens started to be
investigated.
 Doctors had for years empirically utilized various
continuous administration regimens.
 Amenorrhoea and absence of breakthrough bleeding
increase in incidence with extended administration.
Novel approaches to avoid bleeding (3)
 The first extended-cycle oral contraceptive
regimen introduced in clinical practice is an 84-day
regimen that results in bleeding only 4 times a
year.
 A commercial product specifically packed for
continuous use is now available in Europe and
contains 30 μg EE + 150 μg LNG.
 In a variation of this regimen, after administration
of the same combination for 84 days, women are
given 7 pills containing 10 μg EE -Kroll R, Reape
KZ, Margolis M, 2010; Seatle, USA
Novel approaches to avoid bleeding (4)
 A 6-monthly regimen has also been tested: EE
20μg + LNG 100 μg taken with and without a
hormone- free interval- Benagiano G, Carrara S,
Fillippi V, 2009 – Sapienza University, Rome, Italy
 Women in the continuous group reported
significantly fewer bleeding days requiring
protection and were more likely to have
amenorrhea; in addition they also reported
significantly fewer days of bloating and
menstrual pain.
Novel approaches to avoid bleeding (5)
A yearly regimen is now developed:
 Each pill of this novel formulation contains EE 20 μg +
LNG 90 μg to be taken continuously (364 days; 13 cycles)
per year.
 A phase III trial has now evaluated safety, efficacy and
menses inhibition.
 At the end of the 1-year trial amenorrhea was present
in 58.7% cases and a complete absence of bleeding
in 79.0%. Overall, the number of bleeding and spotting
days per pill pack declined with time and adverse events and
discontinuations were comparable to those reported for
cyclic oral contraceptive regimens
Archer DF, Jensen JT, et al, 2006- CONRAD Clinical Research
Center, Eastern Virginia Medical School, Norfolk (USA)
Types of COC (ROMÂNIA, 2010)
(1)
Estrogen
(dose)
Progestogen
(dose)
Trade
name
Pharmaceutical
Company
Ethinyl-estradiol
(0.035mg)
Cyproteron
acetate (2000mg)
Diane 35®
Bayer Schering
Pharma
Ethinyl-estradiol
(0.030mg)
Levonorgestrel
(150 μg )
Microgynon®
Bayer Schering
Pharma
Ethinyl-estradiol
(0.030mg)
Gestoden
(75 μg)
Femoden®
Bayer Schering
Pharma
Ethinyl-estradiol
(0.030mg)
Desogestrel
Marvelon®
Schering Plough
Ethinyl-estradiol
(0.030mg)
Levonorgestrel
(150 μg )
Rigevidon®
Richter
Gedeon
Ethinyl-estradiol
(0.030mg)
Desogestrel
Desorelle®
Richter
Gedeon
(150 μg )
(150 μg)
Types of COC (ROMÂNIA, 2010) (2)
Trade
name
Triquilar®

Pharmaceutical
Company
Phase I
Schering Bayer
Pharma
Ethinyl
estradiol
Ethinyl
estradiol
Ethinyl
estradiol
30μg
40μg
30μg
+
+
+
Triregol ®

Laurina ®
Phase II
Phase III
Levonorgestrel Levonorgestrel Levonorgestrel
Richter
Gedeon
50 μg
6 days
75 μg
5 days
11 days
Schering
Plough
Ethinyl
estradiol
Ethinyl
estradiol
Ethinyl
estradiol
35μg
30μg
+
30μg
+
Desogestrel
Desogestrel
Desogestrel
50μg
7 days
100 μg
7 days
125 μg
+
150μg
7 days
New Types of COC (ROMÂNIA, 2010) (3)
Estrogen
(dose)
Progestativ
(dose)
Trade
name
Pharmaceutical
Company
Ethinylestradiol
(0.035mg)
Norgestimate
Cilest®
Jansen-Cilag
Ethinylestradiol
(0.030mg)
Dienogest
Jeanine®
Bayer-Schering
Pharma
Ethinylestradiol
(0.030mg)
Drospirenone
Yasmin®
Bayer-Schering
Pharma
(250 μg)
(2 mg)
(3 mg)
New Types of COC (ROMÂNIA, 2010)
(3)
Estrogen
(dose)
Progestogen
(dose)
Trade
name
Pharmaceutical
Company
Ethinyl-estradiol
(0.035mg)
Norgestimate
Cilest®
21 tb
Jansen-Cilag
Ethinyl-estradiol
(0.030mg)
Dienogest
Jeanine®
21 tb
Bayer-Schering
Pharma
Ethinyl-estradiol
(0.030mg)
Drospirenone
Yasmin®
21 tb
Bayer-Schering
Pharma
Ethinyl-estradiol
(0.020mg)
Drospirenone
Yaz®
28 tb (24+4)
Bayer-Schering
Pharma
(250 μg)
(2 mg)
(3 mg)
(3 mg)
New Types of COC (ROMÂNIA, 2010) (4)
Estrogen
(dose)
Progestogen
Trade
name
Pharmaceutical
Company
Ethinylestradiol
(0.020mg
Levonorgestrel
100mcg
Loette ®
Pfizer
Ethinylestradiol
(0.020mg
Gestoden
Harmonet®
Pfizer
Ethinylestradiol
(0.020mg)
Gestoden
Logest ®
Bayer-Schering
Pharma
Ethinylestradiol
(0.020mg)
Desogestrel
Mercilon ®
Schering Plough
Ethinylestradiol
(0.020mg)
Desogestrel
Novynette ®
Richter
Gedeon
(dose)
75 μg
75 μg
150 μg
150 μg
Transdermal Administration
FDA approved: Evra ®: delivering daily
 150 μg norelgestromin + 20 μg ethinyl- estradiol
 applied on buttocks, upper outer arm, abdomen or
upper torso but avoiding the breasts
a new patch is applied every week of 3 weeks with a
patch free week to allow the withdraw bleeding
Audet MD, et al, 2001:
 Better efficacy than of low dose COC: 1.2 vs 2.2
pregnancies per 100 woman-years
 Better results when women are < 90 kg
 New application: 5% for partial & 2.8% for complete detachment
Transvaginal Contraception
Vaginal Ring with:
Etonogestrel/etinil-estradiol daily
delivery: o.120mg/0.0015 mg
At every 21 days changed, free 7 days
Nuva-Ring
It is recommended after any other
contraceptive method :
- First day of menstruation : if no other
method
-- In any day after POP
-- In the day when to restart the COC, or
the injectable
-- In the day when the DIU/ implant is
removed
Progestogen only Pills (minipills) (1)





The lowest dose that prevents pregnancy
Alternative for women with estrogens intolerance
Mechanism of action:
Influence cervical mucus and ovarian follicles maturation &
ovulation blockade- in a less degree
Little effects on carbohydrate metabolism &
cardiovascular diseases (thrombosis, migraines, elder
women, smokers)




Disadvantages:  become contraindications
Ectopic pregnancy
Abnormal uterine bleeding: irregular, spotting, amenorrhea
Functional ovarian cysts
Progestogen only Pills (minipills) (2)
Most frequently used during breastfeeding
 19- nor-testosterone derivates:
• Linestrenol 0,5mg- Exluton® x 28 days
• Norehtisterone 350μg - Noriday ® x 28 days
• Levonorgestrel 0,03mg- Microlut ® x 28 days
• Desogestrel 0,075mg- Cerazette ® x 28 days

® = available in România
1 tablet /daily at the same hour;
a delay of 4 hours imposes for 48 hours a back- up form of contraception
Contraindications for POP
 Women with undiagnosed abnormal uterine bleeding,
specially old women
 Ovarian cysts
 Women on different medications, as:
• Carbamazepin
• Felbamate
• Oxcarbamazepin
• Phenobarbital
• Primidone
• Rifabutin
• Rifampin
• Topiramate
• Vigabatrin
Long lasting
Contraceptive Methods
Injectables (1)
Represent a method of contraception with synthetic steroid
hormones; intramuscularly administrated high doses with long
lasting effects, which allow long intervals between doses
 Time of action:
•
•
•
3 months injectable : DMPA:
Depo-Provera®; Megestron®; Depo-Ralovera®: 150mg
2 months injectable : NET- EN: Noristerat®; Norgest®: 200mg
monthly injectable : (estrogen + progestogen):
Cyclofem ®; Mesigyna ®; Lunelle®: 5mg estradiol cypionate
+ 25 mg MPA (USA, 1999)
® available in Romania
Long lasting
Contraceptive Methods
Injectables (2)
Mechanism of action
 Ovulation inhibition: by antigonadotrophic & antiestrogenic
effect; directly ovarian blockade
 Increased cervical mucus viscosity, which becomes a barrier for
spermatozoa
 Changes in tubal rate transport
 Endometrial changes : improper for implantation
Injectables Progestogen Contraceptives
(IPC) (3)
Rates & reasons for discontinuation of use after 12 months for injectables
progestogen contraceptive in WHO studies, 1977-1987
Reason
DMPA
NET-EN
Pregnancy
0.1
0.4
Abnormal bleeding
15. 01
3.6
Amenorrhea
11.9
6.8
Other medical reasons
8.7
9.3
Personal Non medical Reasons
20.7
24.5
Total rate of
discontinuation for use of
IPC
51.4
49.7
Long lasting
Contraceptive Methods
Injectables(4)
Reversibility
delay, but not a loss: fertility recovers at injectable
discontinuation
 Mean time from discontinuation to conception is ~ 9
months, inclusively those 3 months during which the drug is
active; > 90% of women conceive within first 2 years after
DMPA discontinuation
 The delay for fertility recover is shorter for NET-EN than
for DMPA
 Women with amenorrhea during NET-EN use have a longer
delay for fertility recover vs those with regular menses
Long lasting Contraceptive Methods
Injectables (5)
Interferences & interactions (a)
Lipids and lipoproteins:
 No effect, or reduction of triglycerides and total cholesterol (in
connection to antiestrogenic effect of Pgs)
 DMPA  decrease with 10-l5% of HDL- cholesterol, HDL2, HDL3 , Apo Al and
Apo Bl00.
 NET-EN  decrease with 25% of HDL- cholesterol
Carbohydrates:
 No report of overt DM after use of DMPA, even if progestogens
induce the reducing of oral glucose tolerence, hyperinsulinemia and insuline
resistence.
Proteins:
 No interference with synthesis of globulins, angiotensinogen
(some exceptions for NET-EN), fibrinogen, clotting factors: II,
VII, X, XII, XIII, antithrombine III and anti-factor Xa
Long lasting Contraceptive Methods
Injectables (6) Interferences & interactions (b)
3,857 women : 150 mg DMPA at
11,631 patients: 150 mg DMPA at
every 3 months during a average time
every 3 months during a average time
of 12 months
of 12 months
Platelets
No influence
Prothrombin
Time
No influence



15 developed clotting disorders or
other types of thromboembolic
disease
Reducing intervals between doses: 10 /8 weehs for DMPA, when
is used rifampin – a strong enzyme inducer
Changing injectables with other methods when are long time
users of anticonvulsivants (phenytoin, carbamazepine, barbiturates,
pirimidone).
Aminogluthetimid (Cytadren®)
reduces injectables’ efficacy
– an antineoplastic drug
Progestogen Injectable Contraceptives (7)
Relation with pathology: Cardiovascular Risk
Hypertensive Risk
 American Heart Association: long
Thrombotic Risk
time use of DMPA reduces arterial
dilatation and increases the risk for
IPC  first choice for venous CHD, because estrogens low levels
(a)
thrombosis:
 Poulter NR,1998: case-
control international
multicentric study for
WHO:

no or minimum risk for
stroke, venous
thrombembolism,
myocardial infarction
 Pennell D, 2002: DMPA
is safe for
women without cardiovascular
disorders
 Slight decrease of blood pressure
by natriuretic effect of
progestogens
 Severe vascular
migraines/headaches may be
influenced by injectables
Progestogen Injectable Contraceptives
Osteoporosis Risk (b)
(8)
Because of antiestrogenic effect (E < 100 pmol/ml), DMPA influences
the balance osteoresorbtion/osteoformation and induces
osteopenia/osteoporosis, specially after long time use. The effect is
reversible and does not increase fracture risk.
Cross- section Study, 1991: osteodensitometry in women trated with DMPA
comparative to untreated: ↓ BMD with 8% in lombar spine & with 7% in
femural neck
UK, 1998: osteodensitometry for lombar spine and femural neck in women on
DMPA vs untreated of the same age: ↓ with 3% only at lombar spine in treated
(p< 0. 001)
Jean Emans S, 1999: recommends DMPA in teenagers as the second choice and
at minimum 3 years after menarcha in order to have a normal BMI
between 11 şi 15 years, and when it is administered to be associated with
daily supplementation of 1500mg Calcium
Progestogen Injectable Contraceptives
(9)
Relation with pathology
Neoplasias




(c)
Endometrial cancer : ↓ 5 times the risk, protection of
minimum 8 yrs after discontinuation
Epithelial Ovarian cancer : RR=1.1 vs non-users
Cervical cancer: RR= 1.2; DMPA ↑ risk for in situ CC,
reversible, & induced lesions do not progress to invasive
disease. DOES NOT increase the incidence of invasive
cervical cancer: WHO Collaborative Study, 1995
Primary Liver Cancer : RR= 1.1 (Kenya) & 0.3 (Thailand)
Progestogen Injectable Contraceptives
(10)
Relation with pathology : Breast Cancer (d)
 RR=4.6 after long time use at
age < 25 yrs & 3.2-5 before
first full term pregnancy.
 Globally: RR= 1.24 &
doest not increase with
time of use, decrease after
discontinuation
WHO, 1991; Lancet 1996
 DMPA may promote a
breast cancer, which will
appear latter
Patients’
Characteristics
RR
Any use
1.2
Age at
diagnosis
34 yrs
• 35-44 yrs
• > 45 yrs
•
1.4
• 1.1
• 1.0
•
Time since first
use
• < 4 yrs
• 4-8 yrs
• 8-13 yrs
• >13 yrs
2.0
• 1.2
• 0.9
• 1.0
•
Progestogen Injectable Contraceptives (11)
Breast Cancer Risk after DMPA use
WHO, 1991 (e)
Patients’
Characteristics
RR
Age at first use
•
< 25 yrs
<12 months use
12-36 months use
>36 months use
>25 yrs
<12 months use
12-36 months use
>36 months use
Duration of use
< 3 months
4-12 months
13-36 months
>37 months
1.3
• 1.0
• 1.5
• 2.4
• 1.2
• 1.4
• 1.4
• 0.8
•
1.7
• 1.2
• 1.3
• 0.9
•
Progestogen Injectable Contraceptives
Advantages











(12)
High efficiency: > COC’s
Appropriate – no connection to intercourse
Reversible (with same delay)
Do not have estrogens
Do noy implay genitalia manipulation
↓ menstrual cycle disorders
Protection for PID and candidiosis
Prevention for ectopic pregnancy (ovulation blockade)
↓ functional ovarian cysts
Protection of endometrial cancer
Benefits for women with menstrual scissures
Progestogen Injectable Contraceptives
Disadvantages









(13)
The method can not be stoped once it is administered
Injectable form may be not suitable for some women
Menstrual disorders
Weight gain
Delayed of fertility return
Osteoporosis
Chloasma – after exposure to ultraviolet radiation
Depression
Subjective side effects
Progestogen Injectable Contraceptives
Indications


Venous Thrombembolism or
known blood clotting
abnormalities: SEL

Preparation for surgery

Forgetful pills’ women

Patients in need for maximum
protection after immunisation
against rubela, women partners
of men going to vasectomy,
postpartum patients who avoid
sterilization or still waiting for
tubal sterilization

(14)
During the treatment with
Accutane (induces offspring’s
congenital defects) or during
oral anticoagulant therapy or
valproic acid
Patients with long term
progestogens use, as:
premenstrual syndrome,
endometriosis

Alternative to IUD, in cases with
high risk for IUD (young women
whose male partners have many
other female partners)

Sickle cell anemia
Women with scissures
At woman’s choice


Contraindications for Injectables
Obstetrical/Gynecologic Conditions
Breast feeding < 6 weeks from delivery
Pregnancy
Unexplained abnormal uterine bleedong
Breast Cancer (current)
Chronic diseases /Other conditions
Cardiovascular Conditions
mild ( BP <160/100) to moderate HBP (BP <180/110)
severe HBP (BP >180/110) and/or HBP with vascular disease
CHD and stroke
Severe. reccurent headache, inclusive migrene with neurological signs of focal (at any age)
Diabetes mellitus with rethinopathy, nefropathy, neuropathy
Diabetes mellitus of >20 years
Breast diseases (history of cancer without signs of evolution in the last 5 years)
Hepatites (active); Cirrhosis (severe); Jaundice
Liver tumors (benign/ malignant)
Othosclerozsis
How to use Progestogen Injectable
Contraceptives
 Deep i.m. (buttock, thigh, deltoid muscle); with needle of 2.5- 4
cm lengh & of 21-23 gauge; the area of injection must not be
massed, for not reducing the effectiveness
 In menstruated women: first injection is administered in the
first 5 days of menstrual cycle; when on COC or POP the
injectable can be started whenever is necessary
 Postpartum (breastfeeding or not) the first injection is
administered in the 6th week post delivery
 After miscarriage /post abortion :
• in first trimester: in first 7 days after abortion and is not
imposed an extra method
• in the 2nd trimester: delay of administration to reduce the risk of
prolonged and abundant bleeding
 Time during injections: 90  7 days for DMPA, 60  5 days for
NET-EN
 Accepted delay: maximum 2 weeks
Emergency Contraception
(postcoital, “after morning”)
(1)
Conditions:




First 72 hs after unprotect intercourse,
Only for emergency (NOT RUTINE)
After method application, condom use!!!
Pregnancy suspicion, if period does not
appear in the next three weeks
Emergency Contraception :
A. Worldwide:
Available types (2)
- Danazol® (400; 600 mg/d x 5 days)
- RU 486 (Mifepristone)( 600 mg- single dose)
- Ellaone ® (ulipristal acetate 30mg/tb): in the first 120h after unprotected
sex
- Epostane (3-β hidroxy steroid dehydrogenase inhibitor)
B. România:
•
Progestogen only pills:
Levonorgestrel: 0.75mg x 2 (Postinor 2®) (1 tb /12 hs)
Levonorgestrel: 1.50mg x 1 tb (Escapelle): single dose; 1 tb
•
Estrogen only pills:
Ethinyl-estradiol®: 2-5mg/day x 5 days
Premarin® 10mg/day x 5 days
•
Medicated IUD: levonorgestrel/ progesterone
Mirena
Modern contraception with IUD
(1)

Mechanism of action
Chronic endometrial inflammation
(lyzozomal’s activation)
+

Secondary vasculature changes
 “out of phase” endometrium
 ovo- implantation compromise
 Tube motility acceleration
Modern contraception with IUD
Adverse effects
(2)
 Low abdominal pains (at insertion moment)
 Uterine bleeding
 Infections: PID
 Pregnancy: intra and ectopic
 Secondary infertility
 Uterine perforation and miscarriage
Contraindications for IUD (1)
General:
Pregnancy: known or suspected
Abnormalities of the uterus resulting in distorsion of the uterine cavity
Acute PID or history
Postpartum endometritis or infected abortion in the past 3 months
Known or suspected uterine or cervical malignancy, including unresolved
abnormal Pap smear
Genital bleeding of unknown etiology
Untreated acute cervicitis or vaginitis, bacterial vaginosis, untill infection is
controlled
Patient or her partner has multiple partners
Conditions associated with increased susceptibility to infections with
microorganisms, including: leukemia, AIDS, intravenous drug abuse
Genital actinomycosis
A previously inserted IUD that has not been removed
Modified from Physicians Desk Reference, 2004
Contraindications for IUD (2)
Specific:
 IUD with Cooper:
• Wilson disease
• Cooper alergy
 Mirena*; levosert 20 *
• Hypersensitivity to levonorgestrel
• Known or suspected carcinoma of the breast
• History of ectopic pregnancy or condition that predispose to
ectopic pregnancy
Modified from Physicians Desk Reference, 2004
Natural Contraceptive Methods
(periodic/rhythmic abstinence, self observation) (1)
Calendar Rhythm Method
(Ogino- Knaus method) (a)

8 days of menstrual cycle = fertile days
Ovulation= days: 12-16 of cycle
Oocyte : life of 12- 24 h, is fecundable
Spermatozoa: survival 3 days (maximum 7dys)
in female genital tract
Natural Contraceptive Methods (2)
Calendar Rhythm Method (Ogino- Knaus)
(b)
 regular periods with variation
 Index of variability (i.v.) (27, 28, 29….)
 FMD = LP + duration of the longest cycle


Last day fertile interval = FMD - 12
First day of fertile interval = FMD - (19 + i.v.)
 regular periods without variation

FMD = LP + cycle duration

Last day fertile interval = FMD - 12
First day of fertile interval = FMD - 19

 irregular periods
 FMD = LP + duration of the longest cycle
Intercourse: only 11days before FMD
Natural Contraceptive Methods (3)
Temperature Rhythmic Method

Progesterone effect: the increase with 0.4º F in
the morning basal body temperature, just before
ovulation
last day of basal plateau
Ovulation
2nd or 3rd ↑ body basal temperature
 Cycle of 28 days: intercourse permited: 17- 28 days
cycle
of menstrual
Natural Contraceptive Methods
Cervical Mucus Rhythm Method
(Billings: Eve & John)
(4)
 First days of m.c.: cervical mucus – missing
 Estrogen’s influence: more fluid, but viscous, opaque
 Ovulation ”peak days”: very fluid, clear, elastic: wet vagina
 Progesterone’s influence: less fluid and slow disappear: dry
vagina

Intercourse:
days 2-4 after period
“dry” days after ovulation (3-4 days) till to period
Although this method has not achieved popularity, when it is used accurately,
the first- year failure rate is approximately 3%
Natural Contraceptive Methods
(5)
Symptothermal Method
Preovulatory:
Cervical mucus method = onset of fertile period
2-4 days after
+ period
Postovulatory:
cervical mucus method + temperature method
at 4 days after “peak”
at 3 days of increase from basal level
The use of home kits to detect LH increase in woman’s urine
on the day prior to ovulation may improve the
accuracy of periodic abstinence methods
Hatcher RA, 1998
Patients’ Selection & Assessment
Recommended Procedures (1)
Assessment for appreciation of adecquation
and choose of the most proper method
To assess:



Indications & advantages of the method
The presence of situations which limit method’s
choose
The presence of special issues which impose
supplementary medical examinations
Patients’ Selection & Assessment
Recommended Procedures (2)
History: family, individual ’s physiologic & pathologic,
focused on pe:
 Date of birth
 period’s history (menarcha, regularity, menstrual blood flow, abnormal
uterine bleeding)
 First day of LMP
 Obstetrical history (parity, miscarriages & abortions, date of last
delivery, breast feeding, gestational diabetes mellitus, gestational
hypertension & cholestasis)
Physic examination :
 weight
 blood pressure –

breast examination and women teaching for self breast examination,
without transforming this fact in an excessive ritual
 Bimanual genital examination and cervico vaginal smears
Sterilization
voluntary
Female: 28% (USA)
Male:
o Puerperal Tubal Sterilization
o Non -puerperal Tubal
Sterilization
o Reversal Tubal Sterilization
o Hysterectomy
Surgical/ Laparoscopy
 Transcervical Sterilization
 Intratubal Chemical Methods
 Intratubal Devices
Bilateral vasectomy