LOW AND ULTRA LOW ESTROGEN COMBINED ORAL CONTRACEPTIVES

1. LOW AND ULTRA
LOW ESTROGEN
COMBINED ORAL
CONTRACEPTIVES
Aboubakr Elnashar
Benha university hospital
Egypt
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2. CONTENTS
I. ROLE OF HORMONES IN COC
II. TYPES AND FORMULATIONS OF COC.
III. ULTRA LOW VS LOW ESTROGEN COC
1. EFFICACY
2. CARDIOVASCULAR SIDE EFFECTS
3. BREAST TENDERNESS, NAUSEA , BLOATING.
4. CYCLE CONTROL
5. DISCONTINUATION
6. LIPIDS AND LIPOPROTEINS
7. NON CONTRACEPTIVE BENEFITS
 CONCLUSION
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3. Role of progestagen
I. ROLE OF HORMONES IN COC
COCs work by inhibiting ovulation
Role of estrogen
 Enhances cycle control
through stabilizing the
endometrium1,2
 Inhibits FSH secretion:
inhibition of follicular
development2
 Enhances the ovulation-
suppressing effect of
progestins2
 (Hatcher et al 2007; Kronenberg et al,2008).
 inhibits midcycle LH surge:
prevents ovulation1,2
 Thickens cervical mucus:
impedes sperm2
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4. II. TYPES AND FORMULATIONS OF COC.
 Usually EE combined with a Progestogen
 Progestogens: classified acc to the time of
introduction
1st
generation
2nd
generation
3rd
generation
4th
generation
Norethisterone
(Loestrin®)
Levonorgestrel
(Microgynon®)
Desogestrel
(Marvelon® )
(Mercilon®)
Drospirenone
(Yasmin®
Norocarmen)
(Yaz)
Etynodiol
diacetate (only
in POP)
Gestodene
(Gynera®)
Dienogest
(Qlaira®▼ with
E2valerate)
Norgestimate
(Cilest®)
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9. In the early 1960s: COC
Estrogen doses were reduced
Initially: because of increased risk of ischemic stroke, MI,
and pulmonary embolism with high dose estrogen
preparations
Later: because efficacy has not diminished with lower dose
formulations
The dose of estrogen has been reduced
efficacy could be maintained with lower doses
decrease side effects
increase acceptability.
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10.  First:
The dose of oestrogen has been reduced to 35 or
30 μg
 Second:
 The dose of oestrogen has been reduced to 20
ug in 1973
 Advocated for women with a high risk of CVD
because of smoking or age.
 Advocated for general use.
3. Third
The dose of oestrogen has been reduced to15 μg
 Approved in Europe, South America and
elsewhere
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12. Mercilon Desogestrel (150)
Yaz Drospirenon (3000)
Ariana 15 Gestodene (60)AboubakrElnashar

13. Newer formulations contain
1/5 the amount of estrogen
1/10 the amount of progestin compared to older preparations.
Decreasing EE dose +
Increasing progestogen
selectivity
1. Burkman R et al. 2011.
2. Dhont M.2010
Improve tolerability
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14. III. ULTRA LOW VS LOW ESTROGEN COC
 As an increasing number of clinicians prescribe
20mcg EE OCs for the general population, the
question arises:
Whether these products should
become the standard of care.?
 In order to answer this question, one must consider
 Efficacy
 Safety
 Side effects of these products compared with those
of 30/35mcg EE formulations.
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15. 1. EFFICACY
Gallo et al: Cochrane Database S R. 2013
20 μg Vs >20 μg E
No differences in contraceptive effectiveness
OCs containing 20 mcg of EE combined with
gestodene, desogestrel, or levonorgestrel
effectively inhibit ovulation and
decrease cervical mucus scores.
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16. 2. CARDIOVASCULAR SIDE EFFECTS
Most important adverse events.
1. Thromboembolic events
 Directly related to the dose of estrogen.
Reducing the EE dose from 50 to 30 mcg: 60%
decrease in deaths from CV events.
Reducing the dose of EE to 20mcg: further
diminish the rate of OC related CV events
[Meade, 1980].
Although OCs are associated with an increased risk of VTE,
the absolute effect is very small with the current doses of
estrogen and progestin: outweighed by the contraceptive and
noncontraceptive health benefits of OCs.
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17. DVT
(Lidegaard et al .,2011) AboubakrElnashar

18. 2. Stroke
Dose Matters
Contraindications:
histories of DVT, MI, stroke, or hypertension
Risk of stroke:
50 EE mcg COC: relative risk of 4.4
35 EE COC mcg: No Increased risk
[WHO, 1996; Crook et al, 1999;]
20 EE COC: little or no procoagulatory effect.
[Winkler 1998]
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19. ≥35 years:
an increased risk of hemorrhagic stroke: an odds
ratio greater than 2
Smoking:
{Synergistic interaction between OCs, smoking, and
stroke risk}.
RR: 7.1 [CI, 1.533.0]
Nonsmokers
RR: 0.3 [CI, 0.03.0].
[Hannaford et al, 1994]
30–35 μg EE do activate procoagulation parameters, but
these effects –in nonsmokers– are counter balanced by
anticoagulant activity from the fibrinolytic system, a
compensation that does not occur in smokers.
[Winkler 1998]
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20. 3. MI
Nonsmoking
No increased risk among OC users compared with
nonusers
[Croft et al, 1989].
Smoking
OC users or nonusers had an increased risk of MI.
Hypertension
may interact with OCs to increase the risk of MI.
[Croft and Hannaford, 1989; D'Avanzo et al, 1994]
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21. 3. BREAST TENDERNESS, NAUSEA , BLOATING.
 Common
 Predict
 satisfaction and compliance.
 discontinuation rates: 50% during 1st y of use.
[Rosenberg, 1995]
 attributed to COC use are breast tenderness, headache,
migraine, nausea, nervousness, vomiting, dizziness,
weight gain, acne, tiredness, decline of libido and an
increase in blood pressure.
 These non-specific effects
±no more common in COC users than placebo users (Grimes
2011)
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22. Common in new users.
Decrease after few months use
(ACOG 1995)
(20 ug EE+150ug DESO) = Mercilon
(LammersandOp ten Berg1991)
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23. 20 mcg Vs 35mcg EE
estrogenic side effects: 50% less common
[Rosenberg et al, 1999]
Tolerability profiles are better or comparable
[Endrikat et al, 1997, Sulak et al, 1999]
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24. Difficult to attribute to either the oestrogen or
progestogen component
(Dhont 2010)
Desogestrel Vs drospirenone
Less breast tenderness and nausea
(Lawrie et al, Cochrane SR, 2011)
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25. Weight change
Gallo et al, 2014: Cochrane SR
No evidence supporting a causal association
between COC and weight change.
Most comparisons of different combination contraceptives
showed no substantial difference in weight.
Discontinuation of COC because of weight change did not
differ between groups
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26. 4. CYCLE CONTROL
Extremely important
Poor cycle control:
impairs acceptance and adherence to the
contraceptive.
Diminishing compliance: affect the method’s
effectiveness.
46% of pill users discontinued the method {side
effects or physician recommendations}, and about
12% of these due to bleeding irregularities
(Rosenberg 1998).
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27. Causes:
1. Estrogen dose: a major determinant
2. Progestin: dose and type.
3. Patient characteristics
Estrogen dose
20 μg Vs >20 μg estrogen COC.
more BTB and spotting: compromise cycle control
(Nelson 2007; Gallo et al. Cochrane Database Syst Rev 2011)
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28. Discontinuation rate due to poor cycle control:
20mcg Vs 30 mcg: controversial
Higher (23%) Vs (3.7%).
{Bounds et al, 1979]
Comparable
{Reismann et al,1999] .
Less
{Chavez et al1999].
By cycle 4: Normal cycles
70% Vs 55%
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29. Progestin dose and type.
Levonorgestrel: better cycle control than
norethindrone
Gestodene performs better than desogestrel and
levonorgestrel
(Rosenberg 1992;Maitra 2004).
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30. 5. DISCONTINUATION
Gallo et al: Cochrane SR. 2013
20 μg Vs >20 μg E
higher rates of early trial discontinuation
{1. adverse events such as irregular bleeding
2. increased risk of bleeding disturbances}
Lawrie et al, Cochrane SR, 2011
2nd Vs 1st generation:
less discontinuation
3rd Vs 2nd generation
less discontinuation
less intermenstrual bleeding
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31. Discontinuation Rates in Egypt
Reasons of
discontinuation
Percentage of discontinuation
Results from Egypt demographic
and health survey 2005
Awadalla et al.,2013 AboubakrElnashar

32. 6. LIPIDS AND LIPOPROTEINS
20 mcg EE COC have a more favorable effect
than do higher EE dose OCs
[Young et al, 1999]
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33. 7. NON CONTRACEPTIVE BENEFITS
Protective against
ovarian and endometrial cancers
colon cancer to a lesser extent,
Reduces the incidence of
benign breast disease
functional ovarian cysts
PID
ectopic pregnancy
iron deficiency anemia.
used for the treatment
Dysmenorrhea
irregular or excessive bleeding
acne, hirsutism
endometriosis-associated pain
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34. COC containing 20 mcg EE
:non contraceptive benefits . [Ness et al, 2000 ]
{Non contraceptive benefits
Depend on inhibition of ovulation
not dose dependant }
Side effects are dose dependant
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35. CONCLUSIONS
Ultra low estrogen Vs Low estrogen COC
Same efficacy
Same non contraceptive health benefits
Safer
Fewer estrogenic side effects (Nausea. bloating and
breast tenderness): increased tolerability
 Less cycle control
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