UPDATE TERKINI

KONTRASEPSI PIL
Eka Rusdianto Gunardi
Biran Affandi
Klinik Raden Saleh
Departement Obstetri & Ginekologi
Fakultas Kedokteran Universitas Indonesia/
RSUPN Dr. Cipto Mangunkusumo, Jakarta
Prepared for Comprehensive Contraceptive Technology Update, FKUI , 29 Oktober 2016

OBJECTIVES

STEROID
PILL

Contraception ?

: NON-CONTRACEPTIVE BENEFITS

Combined

Oral Pill containing

CYPROTERONE ACETATE

The

role of CYPROTERONE ACETATE in

Hyperandrogenic women

Affandi B. The role of Cyproterone Acetate in Hyperandrogenic Women.

Indonesian Society of Obstetrics and Gynecologys Annual Meeting, Solo 8-10 August 2016.

CDC , 2014

HORMONAL STEROID
CONTRACEPTIVES
1. PILLS
2. SKIN PATCHES
3. INJECTABLES
4. HORMONE-RELEASING IUDs
5. VAGINAL RINGS
6. IMPLANTABLES
7. EMERGENCY CONTRACEPTION
Affandi B. Kontrasepsi Pil Kombinasi Cyproterone Acetate . Pertemuan PDUI , Jakarta 22 April 2016

THE CONTRACEPTIVE PATCHORTHO EVRA

THE CONTRACEPTIVE VAGINAL RING:NUVARING

Flexible, soft,
transparent ring
with outer
diameter of 54
mm and cross
section of 4 mm

Affandi B. YAZ , Pil KB -Wanita Modern . Batam , 28 Juni 2009

Oral contraceptives
Highly effective
Reduction of menstrual loss
Reduction of pelvic
inflammatory disease

Intrauterine devices

No daily motivation
Long-acting
Estrogen-free
Rapidly reversible

Levonorgestrel
intrauterine system
Affandi B. Mirena, Beyond Contraception. Department of Ob.Gyn. University of Indonesia , Jakarta, August 2008

UNIQUE PRODUCT:
CONTRACEPTION PLUS

New category in contraception

- intrauterine contraception reinvented
- combining the advantages of OC and
IUD
High Potential in Idiopathic Menorrhagia
Endometrial protection during HRT

NORPLANT CAPSULE AND JADELLE

ROD, ACTUAL SIZE

History of Oral Contraception

The first oral contraceptive

developed in Europe was
introduced in 1961 as Anovlar
by Schering AG Berlin. It
contained 50 g ethinyl estradiol
(EE).

ORAL CONTRACEPTIVE PILL

Oral

contraceptive pill is often referred to as

"the pill". The pill is one of the most effective
reversible methods of birth control.
There are two basic types:
1. Combination Pills
2. Progestin Only Pills (Mini-pills)
Affandi B. Kontrasepsi Pil Kombinasi Cyproterone Acetate . Pertemuan PDUI , Jakarta 22 April 2016

ORAL CONTRACEPTIVES - COMPOSITION

Monophasic pill

Sequential pill

Gestagen
Oestrogen

Biphasic pill

Triphasic pill
Progestogen-only-pill
(POP)
0

14

21

28

Days of cycle

Affandi B. Kontrasepsi Pil Kombinasi Cyproterone Acetate . Pertemuan PDUI , Jakarta 22 April 2016

ORAL CONTRACEPTIVE PILLS - MODE OF ACTION

4. Disturbance of tubal function (POP)

1. Inhibition of
ovulation

3. Secretory change
of endometrium:
Inhibition of
implantation

2. Thickening of
cervical mucus
(impaired sperm
motility)
Affandi B. Kontrasepsi Pil Kombinasi Cyproterone Acetate . Pertemuan PDUI , Jakarta 22 April 2016

CYPROTERONE ACETATE: A UNIQUE PROGESTIN

Progestins

Spirolactone

Drospirenone

19nortestosterone

Progesterone
derivatives

Oestranes

Gonanes

Pregnanes

Norethindrone
Ethynodiol diacetate
Lynestronol
Norethynodrel

Norgestrel
Levonorgestrel
Norgestimate
Desogestrel
Gestodene

Medroxyprogesterone
acetate
Mogestrol Acetate
Cyproterone acetate
Dydrogesterone

Affandi B. Kontrasepsi Pil Kombinasi Cyproterone Acetate . Pertemuan PDUI , Jakarta 22 April 2016

Structure of CPA

Cyproterone acetate

Neumann F. The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology,

clinical use and tool in basic research. Exp Clin Endocrinol 1994; 102:1-32

CPA vs. Nortestosterone derivatives

Pharmacological
feature

CPA

19-Nortestosterone
derivatives

Progestogenic

Androgenic

Antiandrogenic

Antigonadotropic

Diane-35 Contraception
1 mg CPA is sufficient to inhibit
ovulation
In 20,523 cycles documented in a
clinical trial only 2 pregnancies
due to intake errors
Very reliable contraceptive:
Pearl Index 0.1
Spona J. et al. Ovulation inhibitory effect of Diane-35, a new antiandrogen-estrogen combination:
in Schindler A. E. et al. New Development Biosciences 3. Berlin: de Gruyter 1987: 51-58.
Aydinlik S. et al. Long-term therapy of signs of androgenisation with a low-dosed antiandrogenestrogen combination. Clin Trials J 1990; 27: 392-402.

Diane-35 Cycle control

Excellent cycle
control with a low
rate of breakthrough
bleeding

50
45
40

in % of patients

35

9% pretreatment rate
of intermenstrual
bleeding was
reduced to 0.7% after
Spotting
9 cycles (n=218)
Breakthrough bleeding

30
25
20
15
10
5

Spotting and
breakthrough bleeding

0
1

12

24

36

Cycles

n at baseline =
1,161

Aydinlik S. et al. Long-term therapy of signs of androgenisation with a low-dosed antiandrogenestrogen combination. Clin Trials J 1990; 27: 392-402.
Aydinlik S. et al. Estrogen reduced ovulation inhibitors in the treatment of acne. Double-blind
comparative study of Diane-35 and Diane. Fortschr. Med 1986; 104: 547-550 and Pharma
Research Report 6669

% of cycles during 9 months treatment

Cycle control favorable

vs. DSG 150g / EE 30g

10

4.2
3.2
2.4
1.4

Diane-35
DSG 150 g +
EE 30 g

Spotting

Breakthrough
bleeding

n = 162

Erkkola R. et al. Ovulation inhibitors containing cyproterone acetate or desogestrel in the

treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 1990; 69 (1): 61-65

More than 400 million cycles used worldwide

Available in more than 90 countries
Diane-35, with ist low steroid content, few side-effects
and excellent effect on acne, seems to be the method of
choice for women with acne accepting an oral ontraceptive.

Carlborg L. Cyproterone Acetate versus levonorgestrel combined with ethinyl estradiol in the
treatment of acne. Acta Obstet Gynecol Scand 1986: (Suppl 134): 29-32.

ANDROGENS
Androgens

are male hormones and

are produced by women as well as
men.
They are responsible for stimulating
the growth of the skin, including the
sebaceous glands that produce oil
(sebum), and the hair that grows from
the skin.

However, if they are produced too much, or if

the skin is particularly sensitive to the
effects of androgens, the sebaceous glands
may produce too much sebum. This can
cause the sebaceous glands to become
blocked, resulting in infection, inflammation
and acne spots.
The androgens may also cause excessive
growth of the hair on the face and body - a
condition known as hirsutism.
Both these problems are common in women
with polycystic ovary syndrome (PCOS).

Prevalence of androgen-related
disorders in women
Most common female endocrinopathy
affecting about 10-20 % of women in the fertile age
characterized by excessive androgen action

Many women with androgenic skin changes have

normal androgen levels
suggesting increased target organ (receptor) sensitivity to
androgens

Hyperandrogenism may be of ovarian or adrenal

origin

Redmond GP: Androgens and womens health. Int J Fertil 1998; 43: 91-97

Signs of androgen-related
disorders in women
Related to skin and hair
seborrhea and acne
hirsutism
alopecia

Associated with PCOS

menstrual disturbances, amenorrhea, anovulation
obesity
metabolic abnormalities
insulin resistance with increased risk of diabetes
mellitus
unfavorable lipid profile
increased risk of cardiovascular disease
Rabe T et al. Treatment of hyperandrogenism in women. Gynec Endocrinol 1996: 10:1-44
Redmond GP: Androgens and womens health. Int J Fertil 1998; 43: 91-97

The 3 steps of androgen metabolism

in women

Adapted from: Beylot C. et al. Oral Contraceptives and Cyproterone

Acetate in Female Acne Treatment. Dermatology 1998; 196: 148-152.

Reasons for androgen-related

disorders in women
Increased secretion of testosterone from the
ovaries or adrenals
Increase in the level of freely circulating
androgens not bound to transport protein (SHBG)
Increased enzyme activity (5-reductase) in target
organs, i.e. increased production of biologically
active dihydrotestosterone (DHT)
Increased sensitivity of the target organs to DHT
Neumann F. The antiandrogen cyproterone acetate: discovery, chemistry, basic
pharmacology, clinical use and tool in basic research. Exp Clin Endocrinol 1994; 102:1-32
Redmond G. Androgens and womens health. Int J Fertil 1998; 43: 91-97

Mechanism of CPA action at

receptor level
Androgen-sensitive
target tissues convert
circulating
testosterone into the
potent androgen DHT
(5dihydrotestosterone)
CPA competitively
displaces DHT and
thus blocks
androgenic stimulation
Adapted from Neumann F. et al. Cyproterone Acetate for the Treatment of Androgenisation. 1989:
Diesbach, Berlin.

Anti-androgenic effect of Diane-35

Receptor level: By competition with binding of
testosterone and DHT to their nuclear receptors
Enzymatic: increasing androgen metabolic clearance
at the hepatic level and reducing the peripheral
activity of 5-reductase at skin level
Antigonadotropic: Reduction of LH secretion and
suppression of ovarian androgen secretion
Increase in SHBG and decrease of free testosterone

The anti-androgenic treatment used most: Diane-35

Pucci E. et al. Treatment of androgen excess in females: yesterday, today and
tomorrow. Gynecol Endocrin 1997; 11: 411-433
Shaw. Dermatological Clinics 1996; 14: 803.

Antiandrogenic potency of CPA vs.

other progestins
CMA

DRSP

DNG

CPA

20

40

60

80

100

Relative antiandrogenic potency (Hershberger

test)
Muhn P. et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity.
Contraception 1995; 51: 99-110
Stlzer W. et al. Tierexperimentelle Charakterisierung des Gestagens Dienogest (STS 557). II. Antigonadotrope, gestagene,
estrogene und antiandrogene Wirkungen. III Jenaer Symposium zur hormonalen Kontrazeption, 1985

Androgenic effect on
pilo-sebaceous unit
The visible effects of androgens result
from their action on the pilosebaceous unit
Altering activity of sebaceous gland and
hair follicles
always stimulatory on sebaceous gland
increasing sebum production

effect on the hair follicle depends on location

body hair follicles stimulated
scalp hair follicles inhibited
no apparent effect in a few areas, e.g. eyebrows
Redmond GP: Androgens and womens health. Int J Fertil 1998; 43: 91-97

Diane-35
(CPA 2 mg / EE 35 g)

Oral contraceptive
and

Q1/02-003

treatment for
androgen-related disorders
in one

Diane-35
(CPA 2 mg / EE 35 g)

Highly effective in the treatment of

androgen-related disorders
based on antiandrogenic effect of CPA
supported by antigonadotropic activity of CPA/EE combination

Very reliable contraception

based on progestogenic effect of CPA and antigonadotropic effect
of CPA/EE combination
comparable to other oral contraceptives

Diane-35 Indication
Androgen-dependent diseases in women
seborrhea
acne
mild to moderate cases of hirsutism
androgenetic alopecia

In women who also need or accept

contraception

Diane-35 in acne: Antiandrogenic effect

on the target tissue
Acne is the most
common skin disease
affecting 80% of
females at some time
after the onset of
puberty

Most patients seem to

have sebaceous glands
that are hypersensitive
to androgens

Leyden J. Therapy for acne vulgaris.

N Engl J Med 1997; 336: 1156-1162

Diane-35 in acne: Normalization rates in

clinical studies (n at baseline 1,161)
Symptom

Cycle 3

Cycle 6 Cycle 12 Cycle 36

Facial Acne

37.8%

72.3%

90.6%

100%

Chest Acne

34.5%

72.8%

88.1%

100%

Greasy skin

42.8%

73.4%

87.4%

100%

Aydinlik S. et al. Long-term therapy of signs of androgenisation with a low-dosed

antiandrogen-estrogen combination. Clin Trials J 1990; 27: 392-402

Diane-35 : Prevent Acne

Diane-35 in acne: Effect on lesion

counts and degree of severity
Baseline

Cycle 6 Cycle 12

(n=40)

(n=37)

(n=37)

Comedones

3.5

1.7*

1.2*

Papules

4.2

1.8*

1.3*

Macules

3.9

1.9*

1.1*

Overall
severity

4.8

2.0*

1.4*

*p<0.01 vs. baseline

severity)

(Mean scores; scoring system 0-9 lesions, 0-8

Fugere P. et al. Cyproterone acetate / ethinyl estradiol in the treatment of acne. A comparative
dose-response study of the estrogen component. Contraception 1990; 42: 225-234

Diane-35 in facial acne: clinical effect

Very good or good therapeutic response in 82% of
patients after 6 cycles (n=740)
Significant decrease (> 50%) in the no. of all lesions (p
< 0.05):

in open and closed comedones in 76% of patients

in papules in 80% of patients
in nodes in 88% of patients
in cysts in 85% of patients

Conclusion: effective treatment for acne for all grades

and all types of lesions

Gollnick et al. The efficacy of oral cyproterone acetate in combination with ethinyloestradiol in acne tarda
of the facial type. Journal of Dermatological treatment 1998; 9: 71-79

Diane-35 in facial acne:

tolerance
Well tolerated (n=740)
Only 3.4% of patients discontinued
treatment because of adverse events
Majority of events described as mild
Incidence decreased with duration of
intake
No clinically significant changes in blood
pressure and body weight
Gollnick et al. The efficacy of oral cyproterone acetate in combination with ethinyloestradiol in acne tarda of the facial type.
Journal of Dermatological treatment 1998; 9: 71-79

Diane-35

Before

4 months after Diane-35

Diane-35 : Cegah Ketombe & Kebotakan

Diane-35

Ludwig 1

Ludwig II

Ludwig III

Diane-35 : Basmi Rambut yang tidak normal

Termasuk rambut
yang lebat di
lengan dan kaki

Hirsutism score
after treatment with Diane-35
Ferriman-Gallwey score before and after treatment with Diane35 in patients with idiopathic hirsutism (n=30) vs. PCOS
(n=20)
25
Hirsutism score (mean)

20

P< 0.05

15

10

PCOS (n=10)
Idiop. H. (n=15)

Baseline

3 months

6 months

Tartagni M. et al. Comparison of Diane-35 and Diane-35 plus finasteride in the treatment of hirsutism.
Fertility and Sterility 2000; 73 (4): 718-723

Successful treatment of hirsutism requires

more time than acne therapy
60 cycles treatment with Diane-35 (n=140)
Acne resolved in all cases after 12-24
cycles
Hirsutism resolved in 69% of cases
Moderate hirsutism in 100% of cases
Severe hirsutism became mild to
moderate in 80% of cases
Falsetti L. et al. Management of Hirsutism. Am J Clin Dermatol 2000 Mar-Apr; 1 (2): 89-99
Falsetti L. et al. Efficacy of the combination ethinyl estradiol and cyproterone acetate on endocrine, clinical and
ultrasonographic profile in polycystic ovarian syndrome. Human Reproduction 2001; 16 (1): 36-42.

Tolerance
Concurrent symptoms and signs before and
during treatment with Diane-35 (n at baseline
1,161)
25

in % of patients

20

15

10

He
ad
ac
he

M
(n
on igr
-m ain
e
ig
ra
in
Na e)
u
Vo sea
Ne m
it
r
Br vou ing
e
s
De ast ne
ss
pr
T
es en
s
si
ve ion
m
Ch oo
lo d
as
m
Ed a
em
a

before treatment
Cycles 1-3
Cycles 4-12

More than 80% of

women did not
experience weight
increase (> 2 kg)
Blood pressure
remained within
the normal range
for
98-100% of
women
Drop-out rate due
to adverse events
was only 11.7%
over 36 months

Aydinlik S. et al. Long-term therapy of signs of androgenisation with a low-dosed antiandrogenestrogen combination. Clin Trials J 1990; 27: 392-402

Diane-35 Safety: Concerns about

feminization of a male fetus
Contraceptive efficacy of Diane-35 very high
34 case reports: exposure of male fetuses to CPA
Boys whose mothers were known to have been treated in
pregnancy with the CPA/EE combination at the critical phase
of sexual differentiation
High-dose CPA was used in 4 of these cases
None of them showed any signs of testicular feminization!

Exclusion of pregnancy before the start of treatment

to avoid any risk (as with other OC)

Diane-35 Long-term safety: Liver

Post-marketing long-term surveillance study with 2,506
patients
602 patients were followed up retrospectively >10 years
after end of therapy
61% of those had received CPA >5 years, 45% >8 years
1,135 women treated for signs of androgenization
mean daily dose: 18 mg vs. 136 mg CPA in men
mean duration: 50 cycles vs. 45 cycles in men
42% of women were given Diane-35
16,721 patient years of observation after the first CPA dose:
no malignant liver tumor was found
no severe liver-related adverse drug reactions were
observed Heinemann L. et al. Safety of Cyproterone Acetate: Report of Active Surveillance.
Pharmacoepidemiology and Drug Safety 1997; 6: 169-178.

Experience and satisfaction

with Diane-35
Worldwide about 35 mio. women have used
Diane-35 for the treatment of acne and
seborrhoe
User survey in Germany (n=159)
93% of women were content with the clinical effects after 6
months
Up to 98% of treatment cycles without bleeding disturbances
Absence of withdrawal bleeding in about 1% of cycles
These values are better than the average reported for regular OC

Emphasis Study 1996, Schering data on file

Cara Pakai

Contoh : Hari pertama haid Anda : hari Senin

Ambil tablet yang dibawahnya ada tanda Sen.
Lanjutkan minum tablet tiap hari dengan mengikuti tanda panah
sampai habis (21 hari)
Berhenti minum tablet selama 7 hari (terjadi haid)
Setelah 7 hari bebas tablet, lanjutkan minum tablet dari kemasan baru
Anda harus mulai minum tablet dari kemasan baru pada hari Senin juga

Mengapa perlu minum

Diane-35 setiap hari?
* Untuk menjamin efektifitas kontrasepsi
* Untuk menstabilkan kadar hormon androgen
* Minum Diane-35
secara teratur setiap hari
untuk menghindari
terjadinya perdarahan
bercak

KESIMPULAN
* Pil KB kombinasi (OC) merupakan kontrasepsi yang paling
efektif
* Diane-35(pil kombinasi E2+CPA) merupakan
pilihan untuk mengatasi masalah kulit (kulit berminyak, komedo,
jerawat, hirsutisme) yang disebabkan
oleh ketidak-seimbangan hormon
androgen dan sekaligus berfungsi
sebagai kontrasepsi
Diane-35(pil kombinasi E2+CPA)
aman sampai dengan usia
menopause