A Randomized Controlled Trial of Oral Naproxen and Transdermal Estradiol for Bleeding in LNG-IUC

The levonorgestrel intrauterine system (LNG-IUC) is one of the most effective, reversible
methods of contraception currently available in the United States. User satisfaction is
overall high , however the most often cited reason for discontinuation is irregular bleeding
. The LNG-IUC has mainly progesteronic effects on the uterine cavity. Morphological changes
of the endometrium are observed, including stromal pseudo-decidualization and glandular
atrophy . These endometrial changes may contribute to the irregular uterine bleeding
experienced by women using the LNG-IUC. Up to 14% of women will discontinue the LNG-IUC
within the 5-year period due to abnormal bleeding and up to 66% of woman who request removal
of the LNG-IUC will do so in the first 6 months of use . Women may be less likely to
discontinue the LNG-IUC due to abnormal bleeding patterns if they are counseled appropriately
beforehand, however the prospect of irregular bleeding with few options for management may
dissuade some women from even trying the LNG-IUC. A recent Cochrane review identified the
need for further investigation into the treatment of irregular uterine bleeding caused by
progestin only contraception .

One treatment for progestin-induced irregular bleeding is the administration of nonsteroidal
anti-inflammatory agents (NSAIDs). A 1999 study showed a significant decrease in the number
of bleeding days in women using the levonorgestrel sub-dermal implant randomized to mefenamic
acid 500 mg compared to placebo . A 2004 study found a 50% reduction in bleeding in depot
medroxyprogesterone (DPMA) users randomized to mefenamic acid versus placebo . There have
been no studies looking specifically at NSAIDs for the prevention or treatment of LNG-IUC
related irregular bleeding. Naproxen is an antiprostaglandin that is commonly used in
gynecological practice for relief of dysmenorrhea and has been used to treat menorrhagia. It
is widely available, inexpensive, well-tolerated and has a low incidence of side effects.

Previous studies have also shown the administration of estrogen alone and estrogen-containing
oral contraceptives to users of subdermal levonorgestrel implants (Norplant®) resulted in
decreased frequency of irregular uterine bleeding , . A prior randomized, controlled trial
found a 0.1mg estradiol patch resulted in the clinical improvement of abnormal bleeding,
however this finding was not statistically significant . A randomized, controlled trial of
DMPA users found the cyclic administration of 0.1mg estradiol patches did not decreases
irregular menstrual bleeding . In this study, the cyclic use of estrogen may have resulted in
lower or inconsistent serum estradiol levels. Additionally, the progestational mechanism of
action is more similar between levonorgestrel subdermal implants and LNG-IUC than depot
medroxyprogesterone. No study has specifically addressed estrogen for treatment of irregular
bleeding with the LNG-IUC.

Inclusion Criteria:

- Must be of reproductive age from 18 to 45 years

- Must be choosing LNG-IUC for contraception

- Must be English-speaking

- Be willing to avoid additional use of exogenous hormones, such as oral contraceptives,
for the duration of the study

- Be willing to avoid additional use of nonsteroidal antiinflammatory drugs, such as
ibuprofen or aspirin for the duration of the study

- Be willing to comply with the study protocol, keep the bleeding diary and comply with
follow-up visits and telephone interviews as scheduled

- Be willing and able to provide informed consent

Exclusion Criteria:

- Known or suspected pregnancy

- Contraindication to estrogen use, such as presence or history of:

- venous thromboembolism

- Arterial thrombosis

- Thrombophilia disorders, or known family history of

- Hypertension

- Migraine headaches with aura or focal neurologic involvement, or any migraine
over age 35 years

- Recent or planned future major surgery which will result in prolonged immobilization
during the study period

- Presence or history of severe hepatic disease or liver tumors

- Known or suspected estrogen-dependent neoplasm

- Vaginal bleeding of unknown etiology

- Any cigarette smoking and age over 35 years

- Contraindications to nonsteroidal anti-inflammatory use, such as presence or history
of:

- Gastrointestinal ulcer disease

- Renal insufficiency or failure

- Aspirin-induced asthma or hypersensitivity reaction

- Systemic lupus erythematosus (SLE) and mixed connective tissue disorders

- Use of anticoagulants

- Cardiovascular disease

- Use of medications that alter estrogen metabolism, i.e. rifampin, certain anti-seizure
medications

- Regular use of an NSAID

- Current diagnosis of menorrhagia, metrorrhagia, symptomatic uterine fibroids, or
endometrial polyp

- Hypersensitivity or allergy to any of the components of the estradiol patch

- Use of injectable contraception within 6 months of the start of the study medication

- Delivery or abortion in the previous 4 weeks

- Prior use of LNG-IUD

- Any condition, that in the opinion of the investigator, would contraindicate study
participation