Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

June 21, 2024 updated by: Halley Wasserman, Children's Hospital Medical Center, Cincinnati
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

11 years to 18 years (Child, Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria for POI patients

The participant must:

  1. Be willing to give informed consent/assent
  2. Have a diagnosis of POI based on 2 elevated serum follicle stimulating hormone (FSH) levels obtained >1 month apart.
  3. Be English-speaking

Exclusion Criteria for POI patients

The participant must not:

  1. Have other chronic disease known to affect bone health (e.g., cystic fibrosis, celiac disease, etc.)
  2. Have an identified secondary cause of ovarian insufficiency
  3. Have POI in the setting of Turner syndrome, Fanconi Anemia, galactosemia, or Perrault syndrome (as associated neurological/medical sequelae could confound baseline measures)
  4. Have used medications known to affect bone metabolism over previous 3 months (e.g. anticonvulsants, chronic use of glucocorticoids, Depo-Provera, oral contraceptive pills)
  5. Be currently pregnant (to be confirmed by pregnancy testing)

Inclusion Criteria for Healthy Adolescent Control Participants

The participant must:

  1. Be similar in age and race group to the idiopathic POI group

    1. Control participants age must be within one year of age from the POI participant at the time of enrollment. Age may be within one year older or one year younger
    2. Race of controls participants will be matched based on race of POI patient participants
  2. Have a BMI within 20% of the BMI of the case-matched participant

  3. If postmenarchal, will be regularly menstruating (cycles between 21-35 days)

    a. if POI participant is <12.5yrs (mean age of menarche) will match with a pre- menarchal control participant

  4. Be English-speaking

Exclusion Criteria for Healthy Adolescent Control Participants

The participant must not:

  1. Have a chronic disease, known to affect bone metabolism (e.g., cystic fibrosis, celiac disease, sickle cell disease, inflammatory bowel disease etc.)
  2. Be receiving medications known to affect bone metabolism over previous three months (e.g. anticonvulsants, chronic use of glucocorticoids, Depo-Provera, oral contraceptive pills, etc.)
  3. Have a learning disability or a developmental delay
  4. Be currently taking any selective serotonin reuptake inhibitors (SSRIs), antipsychotics or have any documented problems with anxiety or depression.
  5. Be currently pregnant (as confirmed by pregnancy testing)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Control Participants
The control group will reflect a comparison group similar to the POI patient group. As bone density, body composition, and cognitive domains continue to mature throughout the teenage years, this comparison group will provide an important metric of normal growth and development.
Experimental: POI Participants
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).
Drug: Transdermal Estrogen
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 Names:
  • Estradiol-estradiol patch

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) of the Lumbar Spine
Time Frame: 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.
Change in bone mineral density and body composition from baseline to 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 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.
baseline to 24 months
Change in Volumetric Bone Mineral Density (vBMD) at the Distal Radius as Measured by Peripheral Quantitative Computed Tomography (pQCT)
Time Frame: 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.
Change from baseline to 24 months
Anthropometrics
Time Frame: 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.
Baseline and 24 months
Change in Lean Mass as Measured by DXA Body Composition
Time Frame: 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 lean mass from baseline to 24 months
Change in Symptoms of Anxiety as Measured by Screen for Child Anxiety Related Disorders (SCARED)
Time Frame: 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 from SCARED score baseline to 24 months
Change in Symptoms of Depression as Measured by Child Depression Inventory-II (CDI-II)
Time Frame: 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 from CDI-II score from baseline to 24 months
Change in Memory as Assessed by the Children and Adolescent Memory Profile (CHAMP) Total Memory Index Score
Time Frame: 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 from score from baseline to 24 months
Change in Quality of Life as Assessed by the Child Health Questionnaire-Child Self-Report Form (CHQ-CF87)
Time Frame: 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 from baseline to 24 months
Compliance With Transdermal Estrogen Patch
Time Frame: 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.
Patch Calendars were collected at 6 months, 12 months, 18 months and 24 months. Data presented is through study completion.
Study Medications - Serum Estradiol
Time Frame: Baseline, 12 months, 24 months
Mean serum estradiol levels as measured in participants with POI.
Baseline, 12 months, 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

Patty Brisben Foundation For Women's Sexual Health

Investigators

  • Principal Investigator: Catherine Gordon, MD,Msc, Boston Children's Hospital and Cincinnati Children's Hospital Medical Center
  • Principal Investigator: Halley Wasserman, MD, MSc, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2018

Primary Completion (Actual)

January 5, 2023

Study Completion (Actual)

January 5, 2023

Study Registration Dates

First Submitted

May 11, 2018

First Submitted That Met QC Criteria

June 14, 2018

First Posted (Actual)

June 26, 2018

Study Record Updates

Last Update Posted (Actual)

June 25, 2024

Last Update Submitted That Met QC Criteria

June 21, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FP00000706

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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