Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

Phase 3

Completed

Conditions: Primary Ovarian Insufficiency

Interventions: Drug: Transdermal Estrogen

Registration Number: NCT03568708

Lead Sponsor: Children's Hospital Medical Center, Cincinnati

Brief 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 Cincinnati Children's Hospital Medical Center (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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 19

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
POI Participants	Transdermal Estrogen	This group will be participants who have been recently diagnosed with POI. In an open-label fashion, participants with POI will receive Transdermal Estrogen(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).

Primary Outcome Measures

Name	Time	Method
Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) of the Lumbar Spine	Change in bone mineral density and body composition from baseline to 24 months	Change in height adjusted areal BMD Z-score of the lumbar spine from baseline to 24 months within groups. BMI Z-score, calcium intake, vitamin D intake and physical activity were included in the analysis. As DXA BMD Z-scores already include race, age, and sex, these variables were not included in the analysis. Z-scores ranging between -2.0 and 2.0 are considered normal. A Z-score \<-2.0 is considered low. This analysis considers change in Z-score, therefore a high value reflects a greater increase in BMD Z-score.

Secondary Outcome Measures

Name	Time	Method
Change in Volumetric Bone Mineral Density (vBMD) at the Distal Radius as Measured by Peripheral Quantitative Computed Tomography (pQCT)	Change from baseline to 24 months	To assess the appendicular (peripheral) skeleton, pQCT (Stratec XCT 2000, Orthometrix, Inc., White Plains, NY) bone measures were obtained of the non-dominant radius at the 3% and 66% sites. Measurements were acquired with a voxel size of 0.4 mm, slice thickness of 2.3 mm, and scan speed of 25 mm/sec, and analyzed with manufacturer software version 6.
Anthropometrics	Baseline and 24 months	The mean BMI in kg/m\^2 is presented for each study group at baseline and at the 24 months follow up visit to show that there was no significant difference between groups nor a significant change in BMI over the duration of the study.
Change in Lean Mass as Measured by DXA Body Composition	Change in lean mass from baseline to 24 months	Lean mass was obtained from the whole body DXA scan. Change in baseline to 24 months was assessed.
Change in Symptoms of Anxiety as Measured by Screen for Child Anxiety Related Disorders (SCARED)	Change from SCARED score baseline to 24 months	A 41 item self-report tool to assess for anxiety where each question receives a score of either 0, 1 or 2. Range of scores is 0 to 82. A total score of ≥ 25 may indicate the presence of an Anxiety Disorder. A higher score indicates there are more endorsed symptoms of anxiety.
Change in Symptoms of Depression as Measured by Child Depression Inventory-II (CDI-II)	Change from CDI-II score from baseline to 24 months	A brief self-report test that helps assess cognitive, affective and behavioral signs of depression in children and adolescents 7 to 17 years old. Scales include Emotional and Functional Problems, along with subscales of Negative mood/Physical symptoms, Negative Self-Esteem, Interpersonal Problems, and Ineffectiveness. The total score is converted into a T-score (mean=50, standard deviation=10) where a result \>64 is considered elevated. A higher score indicates there are more endorsed symptoms of depression.
Change in Memory as Assessed by the Children and Adolescent Memory Profile (CHAMP) Total Memory Index Score	Change from score from baseline to 24 months	The ChAMP is a norm-referenced test of memory and learning that was designed for use with children, adolescents, and young adults ranging from 5 through 21 years. The ChAMP includes 4 Subtests of visual and verbal memory to generate a total memory index score as a measure of overall memory. The total memory index score ranges from 50-150 with a mean=100 and standard deviation=15. Higher scores indicating better memory. The data presented here is the change in the total memory index score from baseline visit to the 24 month follow up time.
Change in Quality of Life as Assessed by the Child Health Questionnaire-Child Self-Report Form (CHQ-CF87)	Change from baseline to 24 months	The CHQ-87 is an 87-item self-report survey is designed to measure the physical and psychosocial health of adolescents. The total score ranges from 0-100. Higher scores indicate better quality of life. This instrument is reliable and valid for evaluating aspects of health pertinent across age, gender, health condition, and socioeconomic status in adolescents.
Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) at the Whole Body Less Head, Total Hip, and Femoral Neck	baseline to 24 months	To assess changes in bone mineral density DXA height adjusted BMD Z-scores of the whole body less head, total hip and femoral neck were measured. BMI, calcium intake, vitamin D intake and physical activity were included in the analysis. As DXA BMD Z-scores already include race, age, and sex, these variables were not included in the analysis. Z-scores ranging between -2.0 and 2.0 are considered normal. A Z-score \<-2.0 is considered low. This analysis considers change in Z-score, therefore a high value reflects a greater increase in BMD Z-score.
Compliance With Transdermal Estrogen Patch	Patch Calendars were collected at 6 months, 12 months, 18 months and 24 months. Data presented is through study completion.	Participants with primary ovarian insufficiency (POI) were prescribed weekly transdermal estrogen (TDE2) patches and asked to log on a patch calendar when they changed the patch. Patch calendars were reviewed for compliance and weeks where at least one patch was applied were considered to be in compliance. Weeks in compliance generated the numerator whereas total weeks of participation in the study constituted the numerator.
Study Medications - Serum Estradiol	Baseline, 12 months, 24 months	Mean serum estradiol levels as measured in participants with POI.