A Randomized Controlled Trial of Oral Naproxen and Transdermal Estradiol for Bleeding in LNG-IUC
Condition: Contraception; Bleeding
MeSH terms: Hemorrhage
Study type: Interventional

Summary: 
      We hypothesize that the addition of oral naproxen or transdermal estradiol will decrease the
      number of days of unscheduled bleeding experienced by first-time users of the levonorgestrel
      intrauterine system (LNG-IUC) during the first 12 weeks of use compared to an oral placebo.
      The objective of this study is to compare the total number of days of bleeding experienced by
      first time users of the LNG-IUC randomized to oral naproxen or estradiol patch compared to
      those randomized to placebo for the first 12 weeks of use. We will enroll women initiating
      LNG-IUC to one of 3 groups, transdermal estrogen, oral naproxen or oral placebo. We will
      enroll a total of 114 women, 38 in each group. Women will keep bleeding diaries for 16 weeks
      which will be used to calculate the total number of bleeding or spotting days. Statistical
      analysis will be performed to evaluate if there is less bleeding among the treatment arms
      then the placebo arm.
    

Detailed description: 
      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.
    

Intervention name(s): transdermal estradiol; naproxen; oral placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): transdermal estradiol 0.1mg patch to be changed weekly for 12 weeks.; naproxen 500mg by mouth twice daily for the first 5 days of every 4 week period for a total of 12 weeks; oral placebo to be taken by mouth twice daily for the first 5 days of a 4 week block for a total of 5 weeks
Other intervention name(s): Climara; Naprosyn, Anaprox
Intervention MeSH terms: Naproxen; Estradiol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: contraception; progestin contraception; intrauterine contraception; unscheduled bleeding; placebo