Primary Ovarian Insufficiency: Phenotype and Optimal Treatment
Condition: Primary Ovarian Insufficiency
MeSH terms: Primary Ovarian Insufficiency; Menopause, Premature
Study type: Interventional
Phase: Phase 3

Summary: 
      This pilot study will observe the progression of newly diagnosed POI patients physical and
      psychology outcomes after initiating standard of care HRT treatment in comparison to healthy
      female control participants' physical and psychology health over 24 months.
    

Detailed description: 
      Background: Primary ovarian insufficiency (POI) is an enigmatic condition that affects
      ~1/10,000 women by age 20. Sometimes referred to as "early menopause," POI is characterized
      by estrogen deficiency among other hormonal abnormalities that resemble the menopause. POI is
      a serious chronic condition with no cure. The clinical presentation or 'phenotype' in
      adolescents is not well understood. Health consequences may include delayed or arrested
      puberty, skeletal losses, and the threat to reproductive health. Both the metabolic and
      emotional sequelae are substantial, and one of the most concerning is compromised bone
      health. The optimal hormone replacement therapy (HRT) regimen for these young women is
      debated and practice varies among health providers. Importantly only sparse data exist to
      guide clinicians to make evidence-based decisions regarding the management of these patients.
      If initiated early, HRT may prevent estrogen-associated bone loss.

      Impact: Better understanding of POI may lead to improved treatments for this underserved
      population and have significant implications for the treatment of estrogen deficiency in
      other populations of adolescents and young women, and for all women going though natural
      menopause later in life. Little is known about the effects of HRT on bone health, body
      composition, cognition, and health-related quality of life, especially among adolescents.
      Understanding how this therapy affects these multiple health outcomes will fill knowledge
      gaps regarding treatment for young patients with POI, with potential implications for
      adolescents and young women with estrogen deficiency in other clinical settings. We will
      define the clinical presentation (i.e., phenotype) of adolescent POI. The pilot data
      collected will be used in a future application to the National Institutes of Health, to fund
      a larger trial that builds on observations from this initial study. The information gained
      from this pediatric model may also provide insights on management of the natural menopause
      that occurs in all women later in life.

      Methods: Ten adolescents with idiopathic POI (i.e., from unexplained causes) will be
      recruited through the CCHMC Teen Health Center, Endocrine or Pediatric/Adolescent Gynecology
      Clinics. Ten healthy controls will be recruited from the Teen Health Center. Participants
      with POI will receive transdermal estrogen replacement (beginning at 25 µg/patch applied
      weekly), with the dose increased at subsequent study visits that will occur at 3, 6, 12, 18,
      and 24 months. All data collection will take place at the CCHMC Schubert Research Clinic. The
      investigators will measure bone density of the central skeleton and body composition by
      dual-energy x-ray absorptiometry. To evaluate the peripheral skeleton, bone and muscle
      measures will be obtained by peripheral quantitative computed tomography. At each visit, the
      participants will have blood drawn to measure circulating hormone levels that are
      characteristically altered in adolescents with POI, along with safety assays. Cognitive
      functioning will be assessed using standardized tools. Participants will complete quality of
      life assessments, along with nutrition and physical activity surveys. Lastly, all
      participants will also complete a detailed medical history and health assessment.

      Implications/Future Directions: Once the phenotype of adolescent POI is more clearly defined,
      a logical next question will be to determine whether negative health outcomes can be
      prevented or modified. Data from the proposed trial will guide the design of future
      prospective studies that evaluate the effects of traditional treatments (e.g., HRT),
      including a longer study to monitor HRT therapy, as well as more experimental treatments
      (e.g., skeletal agents) that may benefit young women with this rare condition. In addition,
      findings are expected to open avenues of research for adolescents and women with estrogen
      deficiency in other clinical settings.
    

Intervention name(s): Transdermal Estrogen
Intervention type(s): Drug
Intervention description(s): In an open-label fashion, participants with POI will receive transdermal estradiol (beginning at a dose of 25 µg/patch applied weekly), with the dose increased at 3, 6 12, and 18 months (to 37.5, 50, 75, and 100 µg/patch).
Other intervention name(s): Estradiol-estradiol patch
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Estrogens
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primary Ovarian Insufficiency; Hormone Replacement Therapy; Estrogen Deficiency