This document discusses oral contraceptive pills, specifically those containing progestogens like desogestrel. It provides information on the history and development of oral contraceptives, including how progestogen formulations have evolved to reduce androgenic side effects. Clinical trial results are presented showing that contraceptives containing desogestrel have good cycle control and low rates of side effects. Desogestrel is highlighted as having favorable characteristics like high selectivity and specificity for progesterone receptors over other steroid receptors.

1. Contraception, Hormones,
Progestogens: Update
Dr. Jyoti agarwal
Dr. Sharda Jain

2. Over 400 ppts are available on
slideshare.net for use of public/Doctors
www.slideshare.net / Lifecarecentre

3. India’s Population problem is
challanging

4. India alone accounts for 20% of
World’s population
Time bomb is kicking

5. India will soon over take china if we do not have
clear cut policy of Family Planning

6. BIRTH CONTROL PILLS ARE
THEY RIGHT FOR YOU ?

7. Combined Oral Contraceptives ( COC )
Commonly known as “Pill”
• Widely Accepted & Most Effective
Reversible method of Fertility Control
• In 1951, India was the 1st country in world to
introduce COC in National programme of Family
Planning

8. The type of birth control to use is the personal
decision but experts feel if you are sexually
active & do not want to have pregnancy you
should consider birth control pills
as they are very effective

9. Oral Hormonal contraception
• In the 1940s, the American chemist Dr Russell Marker
discovered that some plants contained hormone-like
substances and he began purifying progesterone from
Mexican yams.
• However, progesterone is broken down in the digestive
tract and is not absorbed
• In the 1950s, synthetic versions of the hormone were
developed, known as progestogens
• The first large trial of the combined oral
contraceptive (COC) pill took place in Puerto Rico in
1956
Carol A Quarini, History of contraception, Women's Health Medicine, Volume 2, Issue 5, September–October 2005, Pages 28–30

11. As per Speroff…..
 The estrogen content of the pill is of major clinical
importance.
 Thrombosis is one of the most serious side effects of the pill,
playing a key role in the increased risk of death (in the past
with high doses) from a variety of circulatory problems.
 This side effect is related to estrogen, and it is dose related.
Therefore, the dose of estrogen is a critical issue in selecting
an oral contraceptive.

12. Doses of estrogen have been steadily reduced,
From 150 mcg mestranol (equivalent to 100 mcg EE)
To the COCs of today, which contain </=35 mcg EE
150mcg Mestranol (=100mcg EE)2
50mcg EE
35mcg EE
30mcg EE
20mcg EE
Estrogen component of COCs
functions primarily to provide
stable and predictable cycle
control,
Higher doses of estrogen is
associated with adverse events,
such as nausea, breast tenderness
and bloating

13. As compared to women using 20 mcg preparations, those using the 35 mcg consistently
experienced considerably more frequent estrogenic side effects
This study suggests that 20 mcg OC represent a logical and beneficial doses
0
0.5
1
1.5
2
Nausea
Breast
tenderness
Bloating
Ratio of COC-related symptoms with 35 micrograms of
ethinyl estradiol (EE) relative to 20 micrograms
Relative
risk
ratio
*
*
*
Study Design: Randomized, open-
label multicenter clinical trial
comparing OC Pill containing (20
mcg ethinyl estradiol [EE] with
levonorgestrel), (20 mcg EE with
desogestrel ), and (35 mcg EE with
norgestimate )463 OC starters or
switchers.
Result: Bloating, breast tenderness,
and nausea were approximately 50%
more common in women using 35
mg EE as compared to 20 mg EE
preparations.
95% CI,
1.29 -1.46
RR 1.4
95% CI,
1.44 -1.60
RR 1.5
95% CI,
1.37 -1.89
RR 1.6
P=0.000
P=0.000
P=0.004
Side effects of estrogen increased at higher dose

14. High-dose estrogen COCs linked to
macrovascular risk
0
0.5
1
1.5
2
2.5
3
3.5
Lidegaard Ø et al. BMJ 1993;306:956–963
Odds
ratio
Progestin
only
30–40 mcg
estrogen
50 mcg
estrogen
OC non-
users
Cerebral thromboembolic risk with oral
contraceptives according to estrogen content
OC=oral contraceptive
Study Design: A retrospective
case-control study to assess the risk
of cerebral thromboembolism in
794 women in Denmark aged 15-44
who had suffered a cerebral
thromboembolic attack during
1985-9 and 1588 age in control
matched randomly selected controls.
Result: Combined or sequential
pills containing 30-40 mcg
oestrogen are associated with a
one third reduced risk compared
with preparations containing 50
mcg estrogen.

15. PROGESTOGENS :( 4 Groups )
Norethisterone Group : ( 1st
generation Pills )
• Moderate Androgenic property ….
• Norethisterone,
• Norethisterone Acetate ,
• Lynestrenol
Norgestrel : ( 2nd generation)
• Strong Progestogenic & Androgenic
property….
19 – nor testosterone
derivatives : ( 3rd generation )
• Anti ovulatory function by
suppressingGonadotropin
• Desogestrel,
• Gestodene,
• Norgestimate
4 ) Spironolactone analogue :
• Antiandrogenic & Anti
mineralocorticoid …
• Drosperinone ( DRSP )

16. Evolution of progestogens focused on reducing the
androgenic side effects
• Removal of the 19-carbon from ethisterone to form norethindrone did
not destroy the oral activity, and most importantly, it changed the major
hormonal effect from that of an androgen to that of a progestational
agent
• The new progestins, because of their reduced androgenicity, do not adversely
affect the cholesterol-lipoprotein profile
• Indeed, the estrogen-progestin balance of combined oral contraceptives
containing one of the new progestins even promote favorable lipid changes
• The androgenic properties of these compounds, however, were not totally
eliminated and minimal anabolic and androgenic potential remains within the
structure

17. The ability of any progestin to bind to the progesterone
receptor varies between different compounds and by this,
the biological effect of the progestin is influenced
Relative binding
affinity
Progesterone LNG 3-Keto-DSG DNG DRSP
Progesterone receptor 50 150 150 5 35
Androgen receptor 0 45 20 10 65
Estrogen receptor 0 0 0 0 0
Glucocorticoid
receptor
10 1 14 1 6
Mineralocorticoid
receptor
100 75 0 0 230
Binding affinity relative to: androgen receptor, metribolone=100%; estrogen receptor, estradiol 17=100%; glucocorticoid receptor,
dexamethasone=100%; mineralocorticoid receptor, aldosterone=100%
LNG: levonorgestrel; 3-Keto-DSG: active metabolite of desogestrel (DSG); DNG: dienogest; DRSP: drospirenone
High specificity for PR and low affinity for other
steroid receptors is a desirable attribute

18. Selectivity index
Selectivity index is simply obtained by dividing the progestogenic binding affinity of each compound
by its androgenic binding affinity, thus leading to a ratio of desired and undesired hormonal
properties.
High progestogenic
affinity
Low androgenic affinity
High
selectivity
Index
0
5
10
15
20
25
30
35
40
45
LNG
NET 3-keto-DSG GSD
RBAOrg 2058/ RBADHT
5
8.8
40*
26*
This slide confirms that third generation progestogens are more selective than the
older types and that within this group, 3-keto-desogestrel (which is the active
metabolite of desogestrel) is the most selective progestogen.

19. Desogestrel stands out due to its
remarkable characteristics
Deletion of oxygen molecule at position 3
Addition of methylene group at position 11
• Theoretical Effect
– Oxygen replaced in the liver leads to the active 3-Keto-DSG
– Methylene removes the androgenic side-effects
3
11
Levonorgestrel Molecule
Desogestrel Molecule

20. Evidence Summaries
Randomized
Controlled Double
Blind Studies
Cohort Studies
Case Control Studies
Case Series
Case Reports
Ideas, Editorials, Opinions
Systematic Reviews and Meta-analysis
Accessed on 16-8-12 at http://ebp.lib.uic.edu/applied_health/node/12

21. 13290 healthy, fertile women from
multiple centers
Ob/gyn: contraception
history, BMI, BP, skin
androgenic symptoms
(Desogestrel 150mcg +
Ethinylestradiol 30mcg) 21X7 regimen
Cycle 2
3
4
5
6
F/U of 11605 patients
Outcome:
•Reliability
•Cycle Control
•Side effects
Clinical Evaluation of a Monophasic Ethinylestradiol /
Desogestrel-containing Oral Contraceptive
Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinyl/desogestrel containing oral contraceptive. Arznei Forsch/Drug Res 1988; 38 (II): 932-4
Study Design
 A multicenter trial was
conducted in 267 centers
in Italy to evaluate the
efficacy, acceptability and
safety of a monophasic
oral contraceptive
containing 30 μg ethinyl
estradiol and 150 μg
desogestrel
 13,290 women were to be
followed up for a total of
74,967 cycles.

22. Results:
(N=11,605)
3
25
20
15
1
0
5
0
BTB
spotting
2
1
0 4 5 6
cycle
percentage
The incidence of irregular
bleeding returned to pre-
treatment levels by 3rd cycle
and decreased to 2.9% by 6th
cycle
Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinyl/desogestrel containing oral contraceptive. Arznei Forsch/Drug Res 1988; 38 (II): 932-4
Cycle control:
Efficacy:
•During the total of 74,967 evaluated
cycles only three pregnancies occurred.
•The Pearl Index is 0.0 for method failure
and 0.04 for patient failure.
Cycle Nausea Headache
Breast
tenderness
0 2.2 9.9 7.9
3 4.6 6.9 7.1
6 1.2 2.8 4.9
(Discontinuation rate for subjective side effects 2.3%)
Subjective side effects:

23. Conclusion
• The monophasic oral contraceptive containing 150 μg desogestrel and
30 μg ethinyl estradiol was shown to be very reliable.
• Cycle control was good: The incidence of irregular bleeding returned to
pre-treatment levels by 3rd cycle and decreased to 2.9% by 6th cycle
• The general incidence of minor complaints was lower than reported
before treatment commenced.
Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinyl/desogestrel containing oral contraceptive. Arznei Forsch/Drug Res 1988; 38 (II): 932-4

24. Key
Trials
0.1
13290
Billota and Favilli et al
5.2
1690
Rekers et al
4.0
219
Van Trappen et al
2.9
1221
Walling et al*
5.8
208
Wiseman et al
6.0
475
Dieben et al
2.1
277
Lanchit and fixon et al*
BTB
%
Number
Trial
Irregular bleeding incidence in cycle 6
12 years of clinical experience with an Oral Contraceptive
Containing 30mcg Ethinyloestradiol and l50mcg Desogestrel reviewed using 14 clinical
trials.
• 14 Clinical Trials involving over 44,000
women for more than 1,90,000 cycles
• No pregnancies due to method failure
overall (PI- 0.12)
• Incidence of BTB- 0.1%-6.0%
• Incidence of subjective side effects
were low
• No significant change in hematological
and metabolic changes
• 2-3 fold  in SHBG levels with fall in
testosterone levels
Fotherby.K. Contraception. 1995; 51:3-12
BTB = breakthrough bleeding and relates to % of subjects
except two trials marked' which relate to % of cycles. + =
data not given.
About 90% of subjects maintained regular cycles.
In all trials, the COC was well accepted and the rates of discontinuation were similar to
those in other COC trials.

25. Effect on Lipid profile
Desogestrel-ethinylestradiol,
an oral monophasic
contraceptive clinical and lipid
metabolic effects: A 5-year
experience (Open study)
n=311
(Reproductive age with proven fertility.
No hormonal preparation 3 months prior)
Group I (n=118)
DSG-EE group
Group II (n=134)
LNG-EE group
Group III (n=59)
NET-EE group
group I (n=59)
Monophasic
group II (n=75)
Triphasic
Outcome
Stopped at
40 cycles
Study Completed at 60 cycles
Start
To Group I (n=53)
n=49
Stopped
Material/Methods
Rubio-Lotvin et al, Adv Cont Deliv Syst vol 8;75-88
•Efficacy
•Cycle Control
•Blood Pressure
•Lipid Profile
Group I: 118 pt Desogestrel 150mcg +
Ethinylestradiol 30mcg (Monophasic)
•Group II: Levonorgestrel +Ethinylestradiol
pills:group I: Monophasic pill (150mcg
LNG+30mcg EE)
•group II: Triphasic pill
•Group III: Norethinderone 1mg +
Ethinylestradiol 35mcg (Monophasic)

26. Desogestrel-ethinylestradiol, an oral monophasic contraceptive
clinical and lipid metabolic effects: A 5-year experience
Parameters
and cycle
Group I Group II Group
III
Staining 4.5%* 10.3%** 6.5%***
Spotting 2.3% # 4.8% # # 3.5% # #
#
P<0.001
Breakthrough Bleeding:
Results: Body Weight:
Period Group I Group II Group III
Initial 62 Kg 67 Kg 65 Kg
At 60 cycles 88%
(63±0.6)
86%
(70±3.2)
85%
(66±1.6)
12%
(62±0.5)
10%
(69±2.2)
15%
(67±2.2)
--- 4%
(68±1.2)
---
P<0.001
Blood Pressure:
Rubio-Lotvin et al, Adv Cont Deliv Syst vol 8;75-88
*Cycle 4,5,7 **Cycle 2,4,7,8,10,12 ***Cycle 3,5,8
#Cycle 1,2,3,6 ##Cycle 1,3,8,10,11 ###Cycle 2,4,6,7
•In group I, there was an increase of 0.6 kg in 80% of
the women and a decrease of 0.5 kg in 12%. 8%
showed no change.
•In group II, there was an increase of 3.2 kg in 86% of
the women, 2.2 kg in 10% and 1.2 kg in 4%.
•In group lII, an increase of 1.6 kg in 85% and 2.2 kg in
15% was recorded
No significant effect on blood pressure
was seen in all the three groups

27. Lipid profile
HDL-c (%) Group I
Group II
(monophasic)
Group II
(triphasic) Group III
Normal HDL: 15-45%
HDLc Initial 27.7 26.6 28.9 29.9
HDLc after 40
cycles 36.8 20.3 22.5 27.2
27.7
26.6
28.9 29.9
36.8
20.3
22.5
27.2
0
5
10
15
20
25
30
35
40
Group I Group II
(monophasic)
Group II (triphasic) Group III
HDLc Initial
HDLc after
40 cycles
HDL changes:
Lipid Profile:
T.
Cholest
erol
(mg/dl) Group I
Group II
(Monophasic)
Group II
(Triphasic)
Grou
p III
Normal Value: 130-220 mg/dl
Initial 159.4 167 168.8 176.8
After 40
cycles 163.9 172.9 165.2 165.2
LDL
(%)
Group
I
Group II
(Monophasi
c)
Group II
(Triphasic)
Group
III
Normal LDL: 45-60%
Initial 47.4 55.6 54.9 49.9
After 40
cycles 46.6 56.7 54.7 52.1
There were no alterations of total
lipids and total cholesterol.
LDL-c did not show significant changes
At 40th week, subjects from Group II were stopped from taking
LNG pills due to fall in HDL level. 53 from Group II requested
incorporation in Group I and 49 were stopped completely
} }
%
Rubio-Lotvin et al, Adv Cont Deliv Syst vol 8;75-88

28. Follow up of HDL level in subjects from Group II after stopping LNG
pills
Results:
HDL at cycles Group II (monophasic) Group II (triphasic)
HDLc at 40 cycles (while on LNG-EE pills) 20.3 (±1.0) 22.5 (±1.6)
HDLc after 48 cycles (after discontinuation) 30.2 (±1.7) 29.2 (±1.5)
HDLc after 48 cycles (subjects who requested
incorporation to Group I) 36.5 (±1.2) 34.4 (±1.4)
20.3
22.5
29.2
30.2
36.5
34.4
0
5
10
15
20
25
30
35
40
Group II (monophasic) Group II (triphasic)
HDLc at 40 cycles (while on
LNG pills)
HDLc after 48 cycles (after
discontinuing)
HDLc after 48 cycles (subjects
who requested incorporation to
Group I)
Rubio-Lotvin et al, Adv Cont Deliv Syst vol 8;75-88

29. Conclusion
• 100% contraceptive efficacy with all 3 pills
• No impact on blood pressure with all 3 pills
• Minimal weight change in users of DSG-EE after 5 years of continuous use
• Increase in HDL-c component in DSG+EE is consistent with
consumption
• Anabolic effects of LNG and NET observed
Minimal side-effects, 100% contraceptive efficacy and a favorable lipid profile
make the DSG +EE combination the pill of preference

30. Systematic Review
Evaluation of various low-dose progestogen-containing
COCs and to assess their acceptability based on:
1. Effectiveness
2. Discontinuation rates and reasons for discontinuation
3. Cycle control
4. Side-effects
Lawrie TA, Helmerhorst FM,Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM. Types of progestogens in combined oral
contraception: effectiveness and side-effects. Cochrane Database of Systematic Reviews 2011, Issue 5.

31. Material and Methods
N=
Data collection
and analysis
Selection criteria
Objectives
Background
• Major determinants of effectiveness of OCPs are compliance & continuation
which may be influenced by cycle control and common side effects
• The rationale of this review is to provide a systematic comparison of COCs
containing the progestogens currently in use worldwide
• To compare currently available low-dose COCs containing ethinyl
estradiol and different progestogens in terms of contraceptive
effectiveness, cycle control, side effects and continuation rates
• Randomized trials reporting clinical outcomes were considered for inclusion.
• Excluded studies comparing monophasic with multiphasic pills, crossover trials,
trials in which the difference in total content of ethinyl estradiol between
preparations exceeded 105 μg per cycle and those comparing continuous dosing
regimens.
• Two reviewers independently assessed methodological quality, applied
inclusion criteria and extracted data
• 30 trials with a total of 13,923 participants were included
Lawrie TA, Helmerhorst FM,Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM. Types of progestogens in combined oral contraception:
effectiveness and side-effects. Cochrane Database of Systematic Reviews 2011, Issue 5.

32. Key Results: Desogestrel Vs Levonorgestrel
• Pregnancy rates were similar in both groups.
• Discontinuation due to side-effects including cycle disturbances was more
likely to occur in the LNG group (RR 0.40, 95% CI 0.19, 0.82)
Lawrie TA, Helmerhorst FM,Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM. Types of progestogens in combined oral contraception:
effectiveness and side-effects. Cochrane Database of Systematic Reviews 2011, Issue 5.

33. Key Results: Drospirenone Vs. Desogestrel
• Pregnancy and discontinuation rates were similar in both groups.
• Overall, a similar number of women in both groups reported side effects,
except for breast tenderness which was more common in the DRSP group (5
trials, 4258 women, RR 1.39, 95% CI 1.04, 1.86).
• There was a trend towards more nausea, breast tenderness and vomiting in
the DRSP group (6 trials, 4701 women, RR 1.46, 95% CI 0.96, 2.21).
Lawrie TA, Helmerhorst FM,Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM. Types of progestogens in combined oral contraception:
effectiveness and side-effects. Cochrane Database of Systematic Reviews 2011, Issue 5.

34. Summary
• Pregnancy rates overall were comparable
• Women using monophasic COC’s containing 3rd gen progestogens were less
likely to discontinue than the second-generation group
• Women in the 3rd gen group experienced less inter-menstrual bleeding than
the 2nd gen group
• Compared to Desogestrel (DSG), women in the Drospirenone (DRSP) group
were more likely to complain of breast tenderness and nausea
Lawrie TA, Helmerhorst FM,Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM. Types of progestogens in combined oral contraception: effectiveness
and side-effects. Cochrane Database of Systematic Reviews 2011, Issue 5.

35. Absolute Contraindications…
(WHO Category IV)
• Migraine, with focal Neurological Symptoms
• Severe Hypertension
• Complicated valvular heart disease
• D.M. with vascular complications
• Active hepatitis, liver tumors
• Major Surgery
• Prolonged Immobilization .

36. Indications of Withdrawal :
« Severe migraine
« Visual or speech disturbances
« Sudden chest pain
« Unexplained fainting attack or acute vertigo
« Severe leg cramps
« Excessive weight gain
« Severe depression
« Prior to surgery ( Atleast 6 weeks )

37. Interaction With Drugs…
1) Barbiturates , Sulphonamides, Rifampicin
and Anticonvulsant interfere with OC’s and
failure rate increases
2) Interaction with antidiabetic drugs
3) Vit. C aggravates the effect of COC

38. Conclusion
Higher doses of
estrogen
component have
been associated
with adverse
estrogenic events,
such as nausea,
breast tenderness
and bloating
High
Progestogenic
activity and low
androgenic
activity is a
desirable
attribute of a
progestogen
Desogestrel has a
high selectivity to
progestogenic
receptors and
low selectivity for
andorgenic
receptors
Increase in
HDL-c
component in
DSG+EE,
consistent with
consumption
Minimal side-effects, 100% contraceptive efficacy and a
favorable lipid profile make the DSG +EE combination the
pill of preference

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