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					Progesterone Contraceptives


       Cavidan Gülerman, MD



            Zekai Tahir Burak
  Women’s Education and Research Hospital
                 Ankara
Progesterone contraceptives include;

 Progesterone implant
 Progesterone injections
 Progesterone only pill (Minipill)
 Progesterone intrauterine system (Mirena)
 Emergency progesterone contraception
 (within 72 hours on intercourse)
     Progestin contraceptives
May be preferable in some situations:
 Absolute or relative contraindications to
 estrogen
 Side effects to estrogen-containing hormonal
 contraception
 Lactation
 Comfort and feasibility of formulations for
 long-term use
Contraceptive Implants
Contraceptive Implants: Indications

Want to delay the next pregnancy for at least
2-3 years
Desire a highly effective, long term method of
contraception
Experience serious or minor estrogen-related
side effects with estrogen-progestin
contraception
Have completed their childbearing but are not
yet ready to undergo permanent sterilization
Intend to breastfeed for a year or two
Contraceptive Implants Marketed in
      our country: Implanon
Single-rod implant (4 cm in length and 2 mm in diameter)
made of ethylene vinyl acetat and contains 68 mg of
etonorgestrel (the active metabolite of desogestrel)
Duration of use: 3 years
Pearl index: 0.38 with typical use

Levonorgestrel: Two Rods (Jadelle, five years)
Nestorone: Single Rod (Population Council,
Latin America, two years)
Elcometrine: Single Rod (six months)
Nomegestrol acetate: Single Rod (Uniplant, one year)
Capronor: Biodegredable Levonorgestrel (one year)
              Croxatto HB. Eur J Contracept Reprod Health 2000; 5 Suppl 2: 21-28.
                           Erkkola R. Curr Opin Obstet Gynecol 2007; 19: 547-553.
            The Implanon Rod

       Rate controlling membrane (0.06 mm)

Core                                         2 mm


                      40 mm

Core:          40% ethylenevinylacetate (EVA)
               60% etonogestrel
Membrane:      100% EVA
          Contraceptive Implants:
             Characteristics
Serum levels of etonorgestrel are detectable within
hours of insertion
Rapid return of fertility
   Menstruel cycle returns within three months
Continuous contraceptive protection for three years
Does not contain estrogen
   Appropriate for lactating women after the sixth postpartum
   week



Insertion site is the inner side of the nondominant arm
Requires clinician visit for insertion and removal
                Croxatto HB. Eur J Contracept Reprod Health 2000; 5 Suppl 2: 21-28.
Efficacy
Failure Rate (Percent) During First Year of Use




                           Hatcher R. Contraceptive Technology 2004.
     Contraceptive Implant Efficacy
                                Mean Peak Serum              Etonorgestrel
                                Concentration of          Hormone release rate
                                 Etonorgestrel
Within 8 hours after                 266 pg/ml                    60 mg/day
insertion*

At 12 months                      196-261 pg/ml                   40 mg/day

At 36 months                      156-177 pg/ml                   30 mg/day

Within 1 week after            Below sensitivity of
removal                              assay

*Serum concentrations in increased within 8 hours to levels associated with ovulation
inhibiton

                           The Implanon US Study Group. Contraception 2005; 71: 319-326.
 Contraceptive Implant Efficacy:
     Mechanisms of Action
Supresses ovulation
  Occurs within 1 day of insertion
  Ovulation in <5% of users after 30 months of use

Increases viscosity of the cervical mucous
No pregnancies were reported during 5629
women-years of use



            Bennink HJ. Eur J Contracept Reprod Health 2000; 5 Suppl 2: 12-20.
      Ectopic Pregnancy Rates per
          1000 Women-Years


Non-contraceptive users, all ages                3.0-4.5


Copper T-380 IUD                                   0.20


Implant (Norplant)                                 0.28




                                Glasier A. Contraception 2002; 65: 29-37
Contraceptive Implant: Tolerability
A 2-year study investigated the efficacy and
tolerability of Implanon (n=330)
Reasons for discontinuing participation in the study:
   Irregular bleeding: 13%
   Other adverse events: 23%
Adverse events attributed to the study medication:
   Acne: 14.5%
   Emotional lability: 14.2%
   Headache: 12.7%
   Weight gain: 12.1%
   Dysmenorrhea: 9.7%
   Depression: 7.3%
Implant site symptoms:
   Mild pain of short duration: <5%

                 The Implanon US Study Group. Contraception 2005; 71: 319-326.
                Contraceptive Implant:
                  Bleeding Patterns
                                   Percentage of Patients
Number of         Treatment Days      Treatment Days        Treatment Days
Bleeding or            91-180             270-360               640-730
Spotting Days         (n=566)             (n=554)               (n=547)

No bleeding            19%                 24%                   17%

1-7 Days               15%                 13%                   12%

8-21 Days              30%                 30%                   37%

>21 Days               36%                 33%                   35%




                                              Roseland NJ. Organon USA Inc; 2006
     Contraceptive Implant:
 Effect on Bone Mineral Density
An open, prospective, comparative two-year
study of a single-rod implant (n=44) vs. a
nonhormonal intrauterine device (n=29)
found:
  Essentially similar changes in bone mineral
  density from baseline
  No relationship between 17 b-estradiol
  concentration and changes in bone mineral
  density


                        Beerthvizen R. Hum Reprod 2000; 15: 118-122.
Contraceptive Implant: Administration
 If no hormonal contraceptive has been used in
 past month:
    Insert within 5 days of initiation of menses

 If switching from combination contraceptives,
 insert within 7 days of last active tablet, or
 during the pill-free period
 If switching from a progestin-only method:
    Any day if using the progestin-only pill
    Same day as intrauterine device or implant removal
    On due date for next contraceptive injection
                                  Roseland NJ. Organon USA Inc; 2006
Contraceptive Implant: Summary
One option available in our country
Easy and quick to insert and remove
Efficacy equivalent to sterilization
Safe and rapidly reversible
Irregular bleeding patterns may be a problem for
some patients
Majority of reproductive-age women are candidates,
including adolescents
Appropriate option for those preferring a long-term
progestin-only method and do not want injections or
an intrauterine device
         Implant (Implanon) and
Injectable Contraceptives Administration
    in our Family Planning Clinic ZTB

                    Depot-Medroxyprogesterone
 Years   Implanon            Acetate
 2005      102                281

 2006       47                207

 2007       27                295

 2008       11                 49
Injectable Contraceptives
       Injectable Contraceptives:
Depot-Medroxyprogesterone Acetate (DMPA)

  Depo-Provera-150 mg of DMPA
  via deep intramuscular injection
  in the gluteal or deltoid muscle
  Depo-subQ Provera 104-104 mg
  of DMPA via subcutaneous
  injection into the anterior thigh
  or abdomen
  Duration of protection: 3 months
  (13 weeks)
Injectable Contraceptives:
Depot-Medroxyprogesterone Acetate (DMPA)
Indications:
  At least 1 year of birth spacing desired
  Private, highly effective long-acting
  contraception, coitally independent method
  desired
  Estrogen-free contraception needed
  Breastfeeding
  Sickle cell disease
  Seizure disorders
Injectable Depot-Medroxyprogesterone
    Acetate: Mechanisms of Action
  Inhibits ovulation
    Suppresses levels of follicle-stimulating hormone
    and luteinizing hormone
    Eliminates surges in luteinizing hormone

  Thickens cervical mucus
    Prevents sperm penetration
    Reduces sperm transport in the fallopian tubes

  Atrophies the endometrium

                       Hatcher RA. Contraceptive Technology 2004: 461-494
Injectable Depot-Medroxyprogesterone
          Acetate: Advantages
 Continuous contraceptive for 3 months
    Provides highly effective reversibl contraception
 Does not contain estrojen
    No adverse effects seen among lactating women
    Decreased risk of thrombotic events when compared to combination
    progestin and estrogen contraceptives
 Reduced risk of ectopic pregnancy when compared to no
 contraception; if a pregnancy occurs it is more likely to be
 ectopic
 Minimal drug-drug interactions
 Reduction of menstrual bleeding and lower risk of anemia
 Fewer grand mal seizures and sickle cell crises in those with
 these conditions
                               Hatcher RA. Contraceptive Technology 2004: 461-494
Injectable Depot-Medroxyprogesterone
        Acetate: Disadvantages
  Bleeding irregularity; amenorrhea progressively more
  common
  Weight gain (>2 kg) is common and cumulative
  Depression may occur, but overall rates not increased
  Bone density decreases
  Cannot discontinue method immediately
     Side effects may continue until DMPA clears from the woman’s
     body-approximately 6 to 8 months after the last injection
     Return to fertility may take 6 to 12 months after discontinuation

  Return visits required every 11 to 13 weeks
  Changes in lipid profile
                               Hatcher RA. Contraceptive Technology 2004: 461-494
Injectable Depot-Medroxyprogesterone Acetate (DMPA):
      Changes in Bone Mineral Density Over Time
 Mean Change in Lumbar Spine
   Bone Mineral Density (%)




                                 *


                                                                                           *
                                          *
                                                                                 *
                                                  *

                                                          *       *
                                                                          *
                                  24      48       96     144     192     240     24        48         96
                                               During Treatment                        Posttreatment

                                                                  Weeks
                               *p<0.001
                                                                          Kaunitz AM. Contraception 2006: 90-99
          Injectable Depot-
     Medroxyprogesterone Acetate
Women who use Depo-Provera Contraception 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 Depo-Provera Contraceptive
Injection during adolescence or early adulthood, a
critical period of bone accretion, will reduce 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 (longer than 2 years)
only if other birth control methods are ineadequate
 Return to Fertility After Cessation of Injectable
 Depot-Medroxyprogesterone Acetate (DMPA)




                                                            50th Percentile




*Intrauterine device or other barrier method
                                           Schwallie PC. Contraception 1974: 10: 181-202.
Injectable Depot-Medroxyprogesterone Acetate
  Does Not Increase the Risk of Breast Cancer
  Pooled analyses of two substantial case-
  control studies reported no increased risk of
  breast cancer
     Case-control study conducted in New Zealand
     Multicenter case-control study conducted by the
     World Health Organization

  Overall results:
     Relative risk = 1.1 (95%CI 0.97-1.4)
  Among women aged 25 to 34 years:
     Relative risk = 2.3 (95%CI 1.2-4.3)
                                    Skegg DC. JAMA 1995; 273: 799-804.
                                       WHO. Lancet 1991; 338: 833-838.
Timing of Depot-Medroxyprogesterone
           Acetate Injection
  Initial injection:
     On day 1 to 5 of menstrual cycle
     Immediately or within the first 7 days after an
     abortion

  Reinjection:
     At week 11 to 13
     If injection is missed or late (+14 weeks), back-up
     contraception should be used and absence of
     pregnancy should be confirmed


                        Hatcher RA. Contraceptive Technology 2004; 461-494.
  Injectable Depot-Medroxyprogesterone
Acetate (DMPA): Management of Prolonged
       Spotting or Moderate Bleeding
  Provide reassurance that irregular and prolonged
  bleeding episodes are common during the first
  3 to 6 months of DMPA use

  Consider short-term management
     Combined oral contraceptive for one cycle
     Nonsteroidal anti-inflammatory drug
     Ibuprofen (up to 600 mg 3 times/day for 5 days)
     Other forms of exogenous estrogen for 5 days

  Explain that irregular bleeding may recur
  Assess for nonhormonal causes (cervicitis, uterine
  pathology)
   Injectable Depot-Medroxyprogesterone
     Acetate: World Health Organization
          Medical Eligibility Criteria
Condition                                                    Risk Category*
Smoking                                                                 1
Hypertension                                                            2
History of deep venous thrombosis                                       2
Diabetes                                                                2
Pelvic inflammatory disease                                             1
Sexually transmitted infection                                          1
*1: there are no restrictions for use of the method
 2: the benefits of using the method generally outweigh the theoretical or proven risk


                                                         World Health Organization; 2004.
Emergency Contraception: Indications
 Intercourse within past 72 hours without contraceptive
 protection (independent of time in the menstruel cycle)
 Contraceptive method failure, misuse
    Barrier method dislodgment / breakage
    Missed oral contraceptive pills
    Error in practicing coitus interruptus
 Sexual assault
 Exposure to teratogens (e.g., cytotoxic drugs, live
 vaccine)
 Recommended only as an emergency, individual event
 treatment

                  ACOG Practice Bulletin 69. Obstet Gynecol. 2005; 106: 1443-1451.
         Emergency Contraception
              Effectiveness
Method           Number of pregnancies Reduction (%)

No treatment                80                              -

Combined                    20                             75

Progestin-only              10                             88

IUD insertion                1                             99
If 1000 women have unprotected intercourse once in the
second or third week of their cycle

                        Weismiller DG. Am Fam Physician. 2004; 70: 707-714.
     Emergency Contraception
       Mechanism of Action
Mode of action varies according to the day of
the menstrual cycle which intercourse occurs
and EC is administered
Inhibit or delay ovulation
Have effects after ovulation
  Interference with sperm transport or penetration
  Impairment of corpus luteum
  Endometrial changes may prevent implantation
Have no effect if taken after implantation

             ACOG Practice Bulletin 69. Obstet Gynecol. 2005; 106: 1443-1451.
Progestin – Only Emergency Contraception:
                 Nor-Levo

                                   Nor-Levo
                            (Levonorgestrel 0.75 mg)



  First Dose: Take one tablet within 72 hours of
  unprotected intercourse
  Second Dose: Take the remaining tablet 12
  hours after first dose
  (Traditional, two-dose administration)
                     Weismiller DG. Am Fam Physician. 2004; 70: 707-714.
Single vs. Two – Dose Levonorgestrel: Efficacy




           Prevented pregnancies estimated to occur
                      without treatment

  von Hertzen H. WHO Multicentre Randomised Trial. Lancet. 2002; 360: 1803-1810.
Single-Dose vs. Two – Dose Levonorgestrel: Effect of
            Treatment Delay on Efficacy




               Delay in Treatment After Intercourse (Days)


     von Hertzen H. WHO Multicentre Randomised Trial. Lancet. 2002; 360: 1803-1810.
Single-Dose vs. Two – Dose Levonorgestrel: Side Effects




       von Hertzen H. WHO Multicentre Randomised Trial. Lancet. 2002; 360: 1803-1810.
Hormonal Emergency Contraception:
        Contraindications
 Suspected or confirmed pregnancy (WHO)

 Food and Drug Administration-Relative
 (based on OC labeling, but no data available)
   Clotting problems, venous thromboembolism,
   ischemic heart disease, stroke, migraine, liver
   tumors, breast cancer

 No negative effects on fetal development


                         Grimes DA. Ann Intern Med. 2002; 137: 180-189.
        Progestin-only pills

Desogestrel    75 mg/day   (Cerazette)

Levonorgestrel 30 mg/day   (Microval, Microlut)

Norgestrel     500 mg/day (Ovrette, Neogest)

Norethisterone 350 mg/day (Micronor)

Ethynoidial    500 mg/day (Femulen)
diacetate

				
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