Pharmacology of contraceptives

1. Preventing Unintended Pregnancy:
Prescription and Management of Contraception
Amy Whitaker MD MS
Assistant Professor
Department of Obstetrics and Gynecology
Section of Family Planning and Contraceptive Research
The University of Chicago
ACHA Annual Clinical Meeting, May 2012

2. Financial Disclosures
• I have NO actual or potential conflict of
interest in relation to this educational
activity or presentation.
• I have no affiliation with any of the
companies whose products are mentioned
in this presentation.

3. Learning Objectives
At the end of this session, you should be able to:
• Discuss contraceptive methods with patients, from
most to least effective.
• Evaluate patients to help them select a contraceptive
method that will maximize correct use and
continuation.
• Manage side effects of contraception.
• Identify appropriate patients for use of long-acting
reversible contraception (LARC).

4. Unintended pregnancy
Unintended
Intended
Abortion:
43% of unintended
Unintended birth:
57% of unintended
49%:
51%
3.2 million unintended pregnancies per year in the U.S.
54% of women having abortions report using
contraception in the month they became pregnant
Finer LB, et al. Contraception 2011;84:478

5. Unintended Pregnancy
• Sexually active young adult women are at high risk for
unintended pregnancy
• Highest rate among young adult women & older teens
– 107 / 1,000 women age 20-24 / year
– 103 / 1,000 women age 18-19 / year
• That’s 10% per year!
Finer LB, et al. Contraception 2011;84:478

6. CDC
Medical Eligibility Criteria
Definition
No restriction for use of the method
Advantages of using the method generally
outweigh the theoretical or proven risks
Theoretical or proven risks usually outweigh the
advantages of using the method
An unacceptable health risk if the contraceptive
method is used
Systematic review of evidence – Released 2010
Category
1
4
3
2

7. Long-acting Reversible
Contraception
LARC

9. Etonogestrel Implant
Single Rod – Effective for 3 years

10. Etonogestrel Implant
• Single 40-mm  2-mm rod
• Rod is made of ethylene vinyl acetate copolymer
• Contains 68 mg of etonogestrel
– active metabolite of desogestrel
– releases 60 mcg daily
• Effective for 3 years

11. Contraceptive Mechanism of Action
Mishell J Reprod Medicine 1996

12. Etonogestrel Implant
Efficacy
• More effective than permanent sterilization
– 0.05% typical (and perfect-use) failure
• No pregnancies during 1200 woman-years of
exposure (Pearl Index, 0; 95% CI 0.0-0.2)
• American study of 330 women aged 18-40
– no pregnancies in 2 years
Croxatto HB. Eur J Contracept Reprod Health Care. 2000;5(suppl 2):21
Funk et al. Contraception 2005;71:319
Trussell. Contraception 2011;83:397

13. Etonogestrel implant
insertion and removal
• Inserted as outpatient
– average time 0.5 minutes
– mandatory training by manufacturer
– timing of insertion
• Insert any time in cycle; rule out pregnancy
• Back up method if not within the 1st 5 days of menses
• Average removal time 3.5 minutes
Funk et al. Contraception 2005;71:319.

14. Implanon® and Nexplanon®

15. Etonogestrel Implant
Bleeding Patterns
• Total number of bleeding/spotting days
decreased or similar for majority of users
• Key difference:
– irregularity and unpredictability
• ~20% amenorrhea in 1st year
– Increases to 30-40% after 1st year
Mansour et al. Eur J Contr Reprod Health Care 2008;13S1:13

16. Etonogestrel implant
bleeding patterns
Funk et al. Contraception 2005;71:319.

17. Management of bleeding
Mansour et al. Contraception 2011;83:202

18. Management of bleeding
Mansour et al. Contraception 2011;83:202
1st Choice
Daily COC for 21 days, followed by 7-day break.
Use for up to 3 months.
2nd Choice
High-dose progestin for 21 days with 7-day break
(e.g. medroxyprogesterone acetate 10mg twice daily).
Use for up to 3 months.

19. Management of bleeding
Mansour et al. Contraception 2011;83:202

20. Dronavalli S. 2007

21. Other Side Effects
• Acne
– 17% reported acne
– 1.3% of women discontinued for acne
– 61% of women with acne at baseline reported
improvement, and only 8% worsened
Funk et al. Contraception 2005;71:319.

22. Other Side Effects
• Weight gain
– Overall increase in BMI 0.7kg/m2
• Not a significant increase
– 12.7% of women reported weight gain
– 3.3% of women discontinued for weight gain
Funk et al. Contraception 2005;71:319.

23. Efficacy in overweight women
• No clinical trial data
• Women >130% ideal body weight excluded
• Only total of 134 women > 70kg: no failures
• Small pharmacokinetics study indicates
projection of hormone levels sufficient to
inhibit ovulation
• Not contraindicated in obese women or girls
Edelman A. SFP Guidelines. Contraception 2009;80:583.
Gilliam et al. Contraception. 2011;published abstract

24. Bone Mineral Density
& Etonogestrel Implant
• Implanon does not suppress estrogen levels to
extent that Depo-Provera® does
• Randomized trial of Implanon and copper IUD
– No differences in BMD changes between the two
groups during one year of use
Beerthuizen et al. Human Reproduction 2000;15:118

25. Etonogestrel implant continuation
• Bleeding irregularity is the most common
reason for discontinuation
– U.S. studies: 13-14%
• Overall U.S. continuation rate: 75%-84%
Casey et al. Contraception 2011;3:426

26. Very few
contraindications
• SLE with anti-phospholipid antibodies
• Hepatocellular adenoma
• Discontinue if develops during use:
– Migraines with aura
• Unexplained vaginal bleeding suspicious for
serious condition, before evaluation

27. Appropriate patients
• Women desiring highly effective,
confidential, “forgettable” contraception
• Women who cannot use estrogen
• Tolerant of irregular bleeding
– The importance of counseling

28. Intrauterine Contraception
Copper T 380A (Paragard®)
Levonorgestrel-Releasing Intrauterine System
(Mirena®)

29. Intrauterine Contraception
• Paragard™ (TCu380A)
– Copper IUD
– Use up to 10 years
– Heavier periods
– No hormonal
side effects
• Mirena™(levonorgestrel-
releasing IUS)
– Local Progestin
– Use up to 5 years
– Lighter periods
• Irregular for 3-6
months
– Some systemic effects

30. Copper-releasing IUDs:
Mechanism
• Mass effect, like plastic IUDs
• Copper alters uterine and tubal fluid
– Hinders spermatozoa function / motility
• Inhibits fertilization
– Not an abortifacient
Hatcher, 1998

31. Progestin-releasing IUDs:
Mechanism
• Impairs spermatozoa motility / function
• Inhibits conception
– Unable to recover fertilized ova
– Not an abortifacient
• Thickens cervical mucus
• Atrophy of endometrium
• Impairs tubal motility
• 85% of women are ovulatory
Lahteenmaki, 2000

32. Levonorgestrel-releasing IUS
• Releases 20 mcg per
day of Levonorgestrel
• Hormonal side effects
are rare
• Endometrial
concentrations 200-
800x higher than in
blood
Lähteenmäki et al. Steroids 2000

33. Increasing IUD use
among young women
• 2008: current IUD use
– 3.6% of contraceptors aged 15-19 years
• from 0% in 2002
– 5.9% of 20-24 year olds
• from 1.8% in 2002
• ACOG Committee Opinion December 2007
– IUDs should be offered as a “first-line choice”
for contraception in both nulliparous and
parous adolescents
Mosher et al. National Center for Health Statistics. Vital Health Stat 2010;23(29)

34. Efficacy
• Highly effective: >99% typical use
5-year gross cumulative failure rate
1.4
0.7
1.3
0.6
CuT 380
Mirena
All Sterilization
Post Partum
Salpingectomy

35. Risks –
younger patients
• Insertion may be more difficult in
nulliparous women
• Higher expulsion in adolescents
• May have higher rates of copper IUD
removals due to bleeding and pain
–No evidence this occurs with the LNG-IUS
Deans et al. Contraception 2009
Behringer et al. Contraception 2011;84:e5
Hubacher D. Contraception 2007;75:S8

36. Copper IUDs –
menstrual changes
• Increased menstrual flow
– Increased amount and duration
– Usually no change in hemoglobin
• Increased dysmenorrhea
• Management
– Patience and reassurance
– NSAIDS around clock, start 1 day before menses

37. Progestin IUDs
– side effects
• Hormonal side effects are rare & not more
common than in general population
• Nonetheless, they are reasons given for
discontinuation
• No weight gain

38. IUD Use in the US from
1965-1995
Hubacher, Contraception, 2004

39. IUD and Pelvic Inflammatory Disease Risk
Evidence-Based?
• Re-analysis excluding the Dalkon Shield and
addressing bias = no increased risk
• 3 types of bias in observational studies:
– Inappropriate comparison groups
– Over diagnosis of PID among IUD users
– Inability to control for confounding factors
• WHO analysis of 22,900 women over 8 yrs
– Increased risk in first 20 days after insertion
– No increased risk with continued use
Grimes D. Lancet 2000;356:1013
Farley TM, Lancet 1992;339: 785

40. What about infertility in
nulliparous women?
 Case-control study: 1895 women
 Compared women with tubal infertility to 2
separate control groups
 Non-tubal infertility (infertile controls)
 Primigravid (pregnant controls)
 NO association with past use of Copper IUD
 Adjusted OR 1.0 and 0.9, respectively
Hubacher et al. NEJM 2001

41. IUD candidates
• Prior STI or PID: NOT a contraindication
– Contraindicated: current PID or within the past 3
months / Current cervicitis
• High risk women: screen for infection with GC
or CT prior to insertion
• Adolescence and nulliparity are not
contraindications
– CDC category 2 for age < 20 years & nulliparity
CDC: U.S. Medical Eligibility Criteria for Contraceptive Use. May 2010.

42. Depot Medroxyprogesterone
Acetate

43. Depo-Provera
• 150 mg of depot medroxyprogesterone
acetate; administered deep intramuscular
or
• 104 mg subcutaneous
Q 3 months
• Initiate anytime in cycle; rule out pregnancy
– Back up method for 7 days if injection is not
within 5 days of start of menses

44. DMPA
•Benefits:
–Highly effective: 96%
–Little compliance
required
–Easily concealed
–No decreases in efficacy
in overweight women
•Risks and Side Effects:
–Bleeding irregularities
–Delayed return of fertility
–Weight gain
–Decrease in bone mineral
density

45. DMPA –
bleeding patterns
• Irregular bleeding
– 70% in the first year; 10% thereafter
– Usually light; hemoglobin levels rise
• Most common reason for discontinuation
– Up to 25% in the first year of use
• Management
– Similar to management with Implanon

46. DMPA – bleeding patterns
• Bleeding and spotting decrease progressively
with each reinjection
• Amenorrhea:
– 55% at one year
– 70% at 2 years
– 80% at 5 years

47. DMPA and Weight Gain
• Adult women: 4.3 kg increase over 5 years
– Compared to 1.8 kg increase in copper IUD users
• Early weight gain may predict excessive gain
• Weight gain greater in adolescents who are
overweight (BMI >30) when initiating DMPA
– 20 lb weight gain over 18 months in obese teens
Bahamondes et al. Contraception 2001;64:223.
Le et al. Obstet Gynecol 2009;114:279.
Bonny et al. Arch Pediatr Adolesc Med 2006;160:40.

48. FDA Black Box Warning
Women who use Depo-Provera Contraceptive Injection
may lose significant bone mineral density. Bone loss is
greater with increasing duration of use and may not be
completely reversible.
It is unknown if use of Depo-Provera Contraceptive
Injection during adolescence or early adulthood, a critical
period of bone accretion, will reduce peak bone mass and
increase the risk of osteoporotic fracture in later life.
Depo-Provera Contraceptive Injection should be used as
a long-term birth control method (eg, longer than 2
years) only if other birth control methods are inadequate
(see WARNINGS).

49. DMPA &
Bone Mineral Density (BMD)
• Use of DMPA is associated with loss of BMD
• After stopping, recovery of BMD is seen
– return to baseline in 1-4 years
• No data on fracture risk in women who have
used DMPA in the past
Berenson et al. Obstet Gynecol 2004;103
Scholes et al. Arch Pediatr Adolesc Med 2005;159:139
Harel et al. Contraception 2010;81:281

50. DMPA and BMD
• Position papers:
– WHO1
– ACOG2
– Society of Adolescent Medicine3
• NONE recommend restricted initiation or
continuation
• NONE recommend routine BMD testing
1 WHO Epidemiological Record No. 35, 2005
2 ACOG Practice Bulletin No. 73, 2006
3 Cromer BA et al. J Adolesc Health 2006;39:296

51. Depo-Provera
Few contraindications
• Similar to progestin implant
• Severe hypertension (>160/>100)
• Diabetes with
– vascular disease and / or
– > 20 years disease

52. Appropriate patients
• Women desiring effective, confidential,
method and who can return for injections
• Women who cannot use estrogen
• Tolerant of irregular bleeding
• Special populations
– Sickle cell disease
– Epilepsy

53. Combined Hormonal Contraceptives

54. Combined Hormonal Contraceptives
• Safe for most young women
• Added benefit of regulation of menses
• “Typical-use” effectiveness ~ 92%
–(Do not quote perfect use ~ 99%)

55. Oral Contraceptive Pills
• Commonly reported as most effective method
– 54% of 15-19 year olds who use contraception
– 48% of 20-24 year olds
• Poor continuation
– Up to 50% discontinue within first 3 cycles
– One study found discontinuation 88% at one year
– College students: only 29% still using at 6 months
Mosher et al. National Center for Health Statistics. Vital Health Stat 2010;23(29)
Rosenberg MJ, et al. Contraception 1995;52:137
Zibners A, et al. J Pediatr Adolesc Gynecol 1999;12:90

56. Contraceptive patch
• Weekly transdermal patch
– 20 mcg EE + 150 mcg norelgestromin daily
• Continuous delivery
– Area “under the curve” is 60% > in a 35 mcg pill
– Possible increase in estrogen side effects such as VTE
• Less effective if body weight > 90 kg
Contraception 2005 Sep;72(3):168-74
Abma et al. National Center for Health Statistics. Vital Health Stat 2010;23(30)

57. The vaginal ring
• 3 weeks with 1 week ring-free interval
– or 24-4, or continuous
• Lowest ethinyl estradiol dose (15 mcg EE,
120 mcg etonorgestrel daily)
• Continuous dosing
• Use back-up method if out for > 3 hours
Abma et al. National Center for Health Statistics. Vital Health Stat 2010;23(30)

58. Pharmacokinetics of patch, ring and OCPs

59. Potential advantages of
new delivery systems
• Compliance
– Patch > pill in some studies…but not in others
• Satisfaction
– No consistent differences
• Side effects
– Ring with some improvement in nausea and cycle control
• Continuation and efficacy
O’Connell et al. Clin Obstet Gynecol 2007;50:918
Brache et al. Contraception 2010;82:418.

60. The bad news

61. Weight and
Combined Hormonal Contraceptives
CHC and Weight gain –
 NO LINK
Gallo et al. Cochrane Dbase of Systematic Reviews 2008, Issue 4.
Art. No.: CD003987. DOI: 10.1002/14651858.CD003987.pub3.

62. Weight and Contraceptive Efficacy
Decreased
Efficacy
NO
EFFECT
Limited
data
Pill √
Patch √
Ring √
SFP Guidelines. Contraception 2009.

63. Alternate regimens
• Many options beyond standard 21-7
– 24-4 (e.g. Yaz, Loestrin® 24 Fe)
– 3-month [84-7] (e.g. Seasonale, Seasonique)
– 12-months (e.g. Lybrel)
• Advantages
– Decreased follicular activity
• Potential for increased efficacy
– Fewer bleeding days
• More breakthrough bleeding in first several months

64. Breakthrough bleeding
• Common reason for discontinuation
• With time, improved with extended regimens
• Higher rates in women
– who smoke
– with cervical infections
• Management:
– If near end of cycle, discontinue early
– If severe, consider exogenous estrogen

65. Acne
• All pills studied reduced acne
compared to placebo
Arowojoluet al. Cochrane Database of Systematic Reviews 2009, Issue
3. Art. No.: CD004425. DOI: 10.1002/14651858.CD004425.pub4
• No consistent results regarding different types
of progestins
– Cyproterone (pregnane) may be better than LNG
– LNG may be better than desogestrel (!)

66. Shulman LP. J Reprod Med. 2003.
Chang J. In: Surveillance Summaries. 2003.
Incidence
of
VTE
per
100,000
woman-years
0
20
40
60
Pregnancy High-
dose OC
Low-dose
OC
General
Population
Comparative Risks of VTE

67. Combined Hormonal
Contraception:
Contraindications
• History of a venous thromboembolism
• Known thrombogenic mutations
• Migraines with aura
• Hypertension, esp. if poorly controlled
• Lupus with antiphospholipid antibodies
CDC. Medical Eligibility Criteria for Contraceptive Use

68. Barrier Methods

69. Condoms
• Safe for all young women
• Only method that offers
– PROTECTION FROM STIs
• Not effective enough for contraception
– Typical-use failure is 15%
• Counsel for dual protection from
pregnancy & STIs
15%

70. Summary
• Unplanned pregnancy is common
• The implant and IUDs provide greater:
– Convenience
– Efficacy
• Discontinuation of all methods is high
• Counseling in advance is vital