PIL KONTRASEPSI KOMBINASI: Perkembangan Perkembangan

PIL KONTRASEPSI KOMBINASI:
Perkembangan terkini,
terkini, Resiko dan
Manfaat
Moch.Anwar
Division of Reproductive Endocrinology and Infertility
Departemnt of Obstetrics and Gynecology,
Faculty of Medicine -Gadjah Mada University,
Yogyakarta
1
The early history of the Pill
+
Margareth Sanger
(a nurse)
Introduced the term
“Birth control” into
language in 1914.
A pioneer of the
American birth
control movement.
Katherine Dexter McCormick
(A philanthropist)
Gregory Pincus
( One of the leading authorities in
reproductive biology)
Developing a pharmaceutical
contraceptive
“The pill” has been credited with changing the course of
history not only for women but also the world since its
introduction in 1960.
( Likis: J.Midwifery & women’s health, 2002)
2
World wide use of methods
Fem. Sterilisation
29%
Male Sterilisation
9%
Injectables
IUD
4%
21%
Condoms
9%
Trad. Methods
14%
Pill
14%
WHO 1990
3
Current Contraceptive Users
Indonesia, March 2003
METHODS
USERS
%
INJECTABLES
9,743,550
35.2
PILLs
7,796,474
28.1
IUDs
5,218,196
18.8
IMPLANTABLES
3,156,705
11.4
STERILIZATION
1,515,406
5.5
278,473
1.0
OTHERS
TOTAL
Source: BKKBN, 2003
27,708,804
100.0
4
The development of
combined oral contraception
Phase
- 1 (conventional COCs)
Phase – 2 (Lowering dose of COCs)
COCs)
Phase – 3 (Choices of progestins)
Phase – 4 (Changing the regimen)
5
PHASE -1
(Conventional
COC)
THE ORAL CONTRACEPTIVE PILLS
ESTROGEN
Sodium & Water
retention
PROGESTOGEN
Almost all synthetic
progestogens are devoid of the
anti meneralocorticoid
(anti-MC) effect.
OC
Weight gain & increased
blood pressure
They are unable to
antagonize the salt retaining
effect of estrogens
6
7
The pharmacological development of oral
contraceptive pills follow two significant paths
To reduce the
dosage of Ethynil
Estradiol (EE)
150 ug
To reduce the partial
androgenic and
mineralocorticoid effect
of progestogen
30 ug
First generation
Second generation
Progestogen only pill (POP)
PHASE - 2
Third generation
PHASE - 3
8
PHASE - 2
Progression of deminished hormone in oral
contraception
9
Steroid hormone compound
in oral contraceptive pill
Estrogens
• Ethynil-estradiol (EE)
• Mestranol (3-methyl-eter EE)
• Quinestrol (cyclopethyl-eter EE)
Progestogens
•
1st generation
• 2nd generation
Norethyndrone
Norethynodrel, Norgestrel (LNG), Norethysterone,
Ethynodrel diacetate, Ethynilestrenol (Lynestrenol).
• 3rd generation
Desogestrel, Gestoden, Norgestimate.
• Cyproterone acetate (CPA)- Drosperinone (DRSP).
10
Spectrum of hormonal activities of progestogen
Trends in Endocrinology and Metabolism, 2004
Progestagen
AE
EST
AND
AA
GLU
AM
Progesterone
+
-
-
(+)
-
+
Drosperinone
+
-
-
+
-
+
MPA
+
-
(+)
-
+
-
LevoLevonorgestrel
Nomegestrol
acetate
+
-
+
-
-
-
+
-
-
+
-
-
Progestomimetik kuat
Anti-estrogenik (AE)
Anti-androgenik (AA)
Anti -mineralokortikoid (AM)
11
Hampir semua progestogen bersifat androgenik,
Drospirenon bersifat anti androgenik dan anti mineralokortikoid, menyerupai
progesterone alami
Progestogenic
activity
Androgenic Antiandrogenic AntimineraloAntimineralo- Glucocorticoid
activity
activity corticoid activity
activity
Progesterone
+
-
(+)
+
-
Drospirenone
+
-
+
+
-
Cyproterone acetate
+
-
+
-
(+)
Desogestrel
(active metabolite 33-ketodesogestrel)
+
(+)
-
-
-
Dienogest
+
-
+
-
-
Gestodene
+
(+)
-
(+)
-
Levonorgestrel
+
(+)
-
-
-
Norgestimate
(main metabolite levonorgestrel)
+
(+)
-
-
-
(+), negligible at therapeutic dosages; -, no effect; +, distinct effect;
12
Foldert et al. Eur J Contracept Reprod Health Care 2000; 5: 124-34
Phase - 3
CHOICES OF PROGESTOGEN IN HORMONAL CONTRACEPTION
(Foran TM, J.Paediatric and Gynecol, 2005)
PROGESTOGENS
Older progestogens
Newer progestogens
Norethisterone
Desogestrel and Gestodene
A low potency progestogen
Few problems with weight gain
less acne and mood alteration.
Fairly nonandrogenic
Relatively oestrogenic
Good cycle control
CPA and Drospirenone
Levonorgestrel (LNG)
A more potent progestogen
More androgenic
Good cycle control
Progestogenic
Anti androgenic
Antimineralocorticoid
Mild diuretic effetc.
13
O
Drospirenone
H3C
CH3
H
H
H
O
The chemical structure of Drospirenone is as close
as natural progesterone of the women
14
DROSPIRENONE
(Derivative of 17-α spirolactone)
From a pharmacological, clinical and
physiological point of view, is closely
related to natural progesterone.
(Oelkers, 2002)
Progestogen receptor agonist
No effect on :
An MCR-antagonist
The glucocorticoid receptor
An Androgen receptor antagonist
The estrogen receptor
15
ADRENAL GLAND
C
O
R
T
E
X
15%
Zona glomerulosa
Aldosterone
(Mineralocorticoid activity)
75%
10%
MEDULLA
Zona fasciculata
Cortisol and
Androgen
Zona reticularis
Cortisol and
Androgen
Epinephrine
16
The regulation of body fluids and blood pressure is highly dependent
upon the Renin – Angiotensin - Aldosteron System (RAAS)
Raises blood pressure
Mineralocorticoid activity
The most important function of this system is to prevent excessive sodium
loss and to keep blood pressure normal (Oelkers, 1996;Oelkers et al.,1978)
17
Estrogen will increase edema and body weight
ESTROGEN
OC pill
Synthetic estrogen
Pure estrogen
Angiotensinogen
RAAS
Aldosterone
Sodium & Water
retension
Increased edema
Increased body weight
18
Drospirenone and antimineralocorticoid activity
Estrogens
New OC pill
Liver
Angiotensinogen
Angiotensin I
Angiotensin II
Adrenal gland
O
Drospirenone H C
3
CH3
Aldosterone
H
H
H
Kidney
O
Aldosterone
receptor
antagonist
Antimineralocorticoid
activity
Sodium and water retention
Increased plasma volume
Blood pressure rise
Weight gain
Breast tension and other water
retention-related symptoms
19
EE + DRSP
20
21
SODIUM EXCRETION
22
23
DROSPIRENONE AND
ANTI-- ANDROGENIZATION
ANTI
24
Androgen induced acne
Inflammation
Skin blemishes
ACNE
Microbial
colonization
of duct
Excess sebum
The sebaceous glands
in particular are
highly androgendependent
Blockage
Can not leave
the gland
Over-stimulation of
androgen receptors
Increased circulating
androgens
25
Drospirenone
(Antiandrogenic mode of action)
No Inflammation
NO ACNE
NO
No Microbial
Colonization of duct
Manohara
No excess sebum
O
H3C
CH3
No over-stimulation of
androgen receptors
H
H
H
Drospirenone not only enters the
aldosterone receptors, it is also
capable of occupying the androgen
receptor without activating it as
agonist
Androgen receptor antagonist
O
Drosperinon block
androgen receptor
Circulating
androgens
(Huber,2002)
26
Relative antiandrogenic activity of progestine
Four progestines
with antiandrogenic
properties for
clinical use
100
90
80
70
60
50
40
30
20
10
0
East
West
CPA
= Cyproterone acetate
DNG= Dienogest
North
DSRP=Drospirenon
CMA=Chlormadione acete
CPA
Diane-35
CPA 2mg
EE 35
DNG
DRSP
CMA
Anti-androgenic
Anti-minerocorticoid
Schindler AE: Antiandrogenic
progestins for treatment of signs of
androgenisation and hormonal
contraception. Europ J Obstet
Gynecol and Rep Biol,
112(2004):136-41
Yasmin
YAZ
27
Premenstrual dysphoric dysorder (PMDD)
28
Etiologi PMS/PMDD
Steroid seks
sebagai pemicu
Sistem
SEROTONIN
MOOD
29
Steiner M, et al. J Clin Psychiatry 2000;61:17–21
Premenstrual Symptoms
Letih, lesu, lemah
Nafsu makan
bertambah
Mudah marah (iritabilita)
Gangguan tidur
Kurang bergairah/Kurang
motivasi
Gejala fisik (misal:
“breast tenderness”,
“bloating”, sakit
kepala)
Depresi
Cemas/ansietas
Afektif labil
Gangguan konsentrasi
Diagnostic and Statistical Manual of Mental Disorders, 4th
30 ed.
American Psychiatric Association, 1994
Derajat keparahan
penyakit
BERAT
RINGAN
Premenstrual
symptoms
Premenstrual
syndrome
(PMS)
Premenstrual
dysphoric
disorder
(PMDD)
31
Positive Effect of EE+DRSP on Premenstrual Symptoms
32
PHASE – 4
CONTRACEPTION BREAKTHROUGH
MORE RECENT DEVELOPMENTS HAVE INCLUDED
PHASING THE LEVEL OF HORMONAL EXPOSURE
THROUGH THE TREATMENT CYCLE AND
EXTENDING THE DURATION OF ACTIVE
TREATMENT.
Yasmin
21/7
3 mg drsp/30 mcg EE
YAZ
24/4
3 mg drsp/20 mcg EE
33
A NEW REGIMEN OF 24/4 COC
P
P
P
P
34
Substantial changes of OC
Clinical experience with first drspdrspcontaining combined OC, comprising
drsp 3 mg/EE 30 mcg (Yasmin) in a
traditional 21/7 regimen, showed it to
be an effective and wellwell-tolerated
contraceptive with good cycle control.
( Foidart et al, 2000, Huber et al, 2000 and
Parcey et al, 2000)
35
Regimen 24/4 vs 21/7
Greater ssupression
upression of ovarian activity with
drosperinon-- containing oral
drosperinon
contraceptive in 24/4 regimen
Christine Klipping, Ingrid Duijkers,Dietmar Trummer
and Joachim Marr,
Marr, Contraception 78(2008) 1616-25.
36
EE+DRSP memperbaiki rasio HDL/LDL
J clin Endocrinol Metab 1995; 80: 1816-21
37
OVARIAN ACTIVITY
Correct dose
Error dose
87.8
70.0
55.1
56.0
44.8
44.0
30.0
12.2
Both regimens demonstrated reliable suppression of
ovarian activity, however, it was also confirming the
greater suppression with the 24/4 regimen both in
cycle-2 and cycle-3
38
FOLLICLE SIZE (FLSs)
CORRECT DOSE
21/7
24/4
1. The median diameter of the largest FLSs in cycle-2 was
similar in 24/4 regimen compared with 21/7 regimen.
2. The median diameter of the largest FLSs in cycle-3 was
smaller in 24/4 regimen compared with 21/7 regimen.
39
Summary
From a pharmacological, clinical and physiological point of
view, drospirenon is closely related to natural progesterone.
A new low dose combined OC with DRSP 3mg/EE 20 mcg in 24/4
regimen (YAZ) has high degree of efficacy, a good safety
profile and an accetable bleeding pattern.
To be effective in alleviating the emotional and physical
symptoms associated with PMDD (Premenstrual dysphoric
disorder).
This regimen was associated with greater ovarian
suppression and lower and less variable serum hormone
concentrations and fluctuations in general than the
conventional 21/7 regimen.
The shorter hormonehormone-free interval may increase the
contraceptive safety margin in clinical practice compared
with the conventional 21/7 regimen.
40
41
Endometrial thickness
Dosing
eror
1. Both treatment regimens suppressed growth compared with
pretreatment.
2. The maximum endometrial thickness following intentional dosing
error in 24/4 was similar to that of correct intended dosing in 21/7.
42
Serum concentration of estradiol
10 pg/l
10-33 pg/l
1. Both regimens suppressed production of E2 during the
treatment cycles compared with the pretreament cycle.
2. Serum E2 (24/4) 10 pg/l ---- (21/7) 10-33 pg/l.
43
ESTRADIOL LEVEL
With intentional dosing errors during cycle 3 : the longer the
pill-free interval, the greater the rise in serum E2
44
concentration.
Angka Kejadian (%)
30
YAZ®
25
YASMIN®
20
15
10
5
0
0
Data on file
1
2
3
4
5
6
7
8
9 10 11 12
BLEEDING PATTREN
45
Follicle Stimulating Hormone (FSH)
1. FSH levels were suppressed with active treatment in both
groups relative to the pretreatment cycle.
2. Progesterone was consistently suppressed compared to
pretreatment and to similar extent during cycle 2 and 3
(data not shown)
46
Lutenizing Hormone (LH)
Both regimens suppressed production of LH during the
treatment cycles compared with the pretreament cycle.
47
Cycles (day)
Patient PMDD
Control
Pre-Menstrual Dysphoric Disease
48
The sources of androgens in
women are the following:
1.Direct biosynthesis and secretion by the
ovaries (25%).
2.Direct biosynthesis and secretion by the
adrenal (25%).
3.Extragrandular (peripheral) conversion
from precursors (50%).
4.Androgen secreting tumours.
Schindler AE: Antiandrogenic progestins for treatment of signs of
androgenisation and hormonal contraception.
Europ J Obstet Gynecol and Rep Biol ,112(2004):136-41
49
Factors influencing the extent of
androgenisation by circulating androgens
• Increase secretion of testosterone from ovaries or adrenals
• Increase in the level of freely circulating androgens not bound
to transport protein (SHBG).
• Increased enzyme activity (5α-reductase) in target organs, I.e.
increased production of biologically active dihydrotestosterone
(DHT).
• Increase sensitivity and androgen receptor concentration of the
target organs to DHT
Redmond GP: Androgens and women’s health. Int J Fertil Steril, 1998,43 : 91-97
Schindler AE: Antiandrogenic progestins for treatment of signs of
androgenisation and hormonal contraception. Europ J Obstet
Gynecol and Rep Biol ,112(2004):136-41
50
Prevalence of androgen-related
disorders in women
• Most common female endocrinopathy affecting about 1020% of women in the fertile age
• Many women with androgenic skin changes have normal
androgen levels: Suggesting increased target organ
(receptor) sensitivity to androgen.
•Treatment of symptoms associated with hyperandronism
therefore plays an important role in the prevention and
therapeutic measures.
Redmond GP: Androgens and women’s health.
Int J Fertl Steril1,998,43 : 91-97
51
Signs of androgen-related
disorders in women
• Related to skin and hair
- Seborrhea- acne- Hirsutism- Alopecia
• Manifest as PCOS
- Menstrual disturbanses, amenorrhea, anovulation
- Obesity
- Metabolic abnormalities
* Insuline resistance with increased risk of DM.
* Unfavourable lipids profile
* Increased risk of cardiovascular disease.
* Increased risk of endometrial and breast cancer
Schindler AE: Antiandrogenic progestins for treatment of signs of
androgenisation and hormonal contraception. Europ J Obstet Gynecol and
Rep Biol ,112(2004):136-41
About 65% to 85% of hyperandrogenic women have
PCOS
( The contraception report, 2001)
52
Treatment of signs of androgenisation
The therapeutic antiandrogenic effects are based on the
combination of the antiandrogenic progestins with
ethynilestradiol (EE) as estrogen
1. Antiandrogenic progestine compete at the androgen
receptor with testosterone and 5α-DHT.
2. Increase androgen metabolic clearance at the liver
level and reduced peripheral activation of 5αreductase at the skin level.
3. Reduction of LH secretion, thereby reducing the
ovarian secretion of androgens.
4. Increase of SHBG by EE and thereby a decrease of
free testosterone
Schindler AE: Antiandrogenic progestins for treatment of signs of
androgenisation and hormonal contraception. Europ J Obstet
Gynecol and Rep Biol ,112(2004):136-41
53
Benefit of antiandrogenic progestins combined with EE
1. 60% reduction of dysmenorrhoea.
2. Correction of menstrual cycle disturbances.
3. Avoidance or correction of anaemia.
4. Reduction of the rate of imflammatory disease.
5. Risk reduction for fibrocystic breast disease
6. Risk reduction for endometrial and ovarian cancer.
7. Favourable effects on carbohydrate and lipid metabolism.
8. Highly effective contraception
9. Improvement of ovarian size and structure ( decrease of
multifollicularity and stromal hyperplasia)
10. Post-treatment menstrual cycle improvement.
Schindler AE: Antiandrogenic progestins for treatment of signs of
androgenisation and hormonal contraception. Europ J Obstet
Gynecol and Rep Biol ,112(2004):136-41
54
JAZ !
I CAN
55

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