Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

Study Overview
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Brief Summary
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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
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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.

Official Title
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Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

Conditions
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Primary Ovarian Insufficiency

Intervention / Treatment
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* Drug: Transdermal Estrogen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for POI patients The participant must: Be willing to give informed consent/assent Have a diagnosis of POI based on 2 elevated serum FSH levels obtained >1 month apart Be English-speaking Exclusion Criteria for POI patients The participant must not: Have other chronic disease known to affect bone health (e.g., cystic fibrosis, celiac disease, etc.) Have an identified secondary cause of ovarian insufficiency Have POI in the setting of Turner syndrome, Fanconi Anemia, galactosemia, or Perrault syndrome (as associated neurological/medical sequelae could confound baseline measures) Have used medications known to affect bone metabolism over previous 3 months (e.g. anticonvulsants, chronic use of glucocorticords, Depo-Provera, oral contraceptive pills) Be currently pregnant (to be confirmed by pregnancy testing) Inclusion Criteria for Healthy Adolescent Control Participants The participant must: Be similar in age and race group to the idiopathic POI group 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 Race of controls participants will be matched based on race of POI patient participants Have a BMI within 20% of the BMI of the case-matched participant 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 Be English-speaking Exclusion Criteria for Healthy Adolescent Control Participants The participant must not: Have a chronic disease, known to affect bone metabolism (e.g., cystic fibrosis, celiac disease, sickle cell disease, inflammatory bowel disease etc.) 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.) Have a learning disability or a developmental delay Be currently taking any SSRIs, antipsychotics or have any documented problems with anxiety or depression. Be currently pregnant (as confirmed by pregnancy testing)

Ages Eligible for Study
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Minimum Age: 11 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control Participants<br>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<br>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<br>* 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).<br>* Other names: Estradiol-estradiol patch;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DXA Measure of Bone Mineral Density | DXA measures of the lumbar spine | Change in bone mineral density and body composition from baseline to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Medications - patches | Compliance with study medications as assessed by patch count at study visits | Adherence with intervention from baseline to 24 months | 
| Study Medications - serum estradiol | Compliance with study medications as assessed by serum estradiol levels. | Change in serum estradiol levels from baseline to 24 months | 
| pQCT | To assess the appendicular (peripheral) skeleton, bone measures of the non-dominant radius will be obtained by pQCT | Change from baseline to 24 months | 
| Bone age | Radiograph of the left wrist to assess bone age for POI participants | Change from baseline to 24 months | 
| Anthropometrics | BMI in kg/m^2 | Change from baseline to 24 months | 
| Youth/Adolescent Questionnaire (YAQ) | Nutrition survey | Change from baseline to 24 months | 
| Child Health Questionnaire-Child Self-Report Form (CHQ-CF87) | The tool consists of 12 summated subscales and is designed to measure the physical and psychosocial health of adolescents. The subscales include change in health in the last year, bodily pain, behavior, mental health, among others. Items are scored from 0-100, except for the change in health during the last year, and family cohesion variables, which are scored from 1-5. Higher scores on all other variables indicate better quality of life. This instrument has a record of reliability and validity for evaluating aspects of health that are pertinent across age, gender, health condition, and socioeconomic status in adolescents | Change from baseline to 24 months | 
| Menopause Rating Scale (MRS) | 11-item self-report validated measure to assess symptoms associated with menopause. The composite scores for each of the dimensions (sub-scales) is based on adding up the scores of the items of the respective dimensions. The composite score (total score) is the sum of the dimension scores. The three dimensions, their corresponding questions and the evaluation are detailed and summarized. The total score of the MRS ranges between 0 (asymptomatic) and 44 (highest degree of complaints). psychological symptoms: 0 to 16 scoring points ( 4 symptoms: depressed, irritable, anxious, exhausted) somato-vegetative symptoms: 0 to 16 points (4 symptoms: sweating/flush, cardiac complaints, sleeping disorders, joint & muscle complaints) urogenital symptoms: 0 to 12 points (3 symptoms: sexual problems, urinary complaints, vaginal dryness). | Change from baseline to 24 months | 
| Child Depression Inventory-II (CDI-II) | 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. Higher scores indicate more depressive symptoms for total scoring and subscale scores. | Change from CDI-II score from baseline to 24 months | 
| Screen for Child Anxiety Related Disorders (SCARED) | A 41 item self-report tool to assess for anxiety. A total score of ≥ 25 may indicate the presence of an Anxiety Disorder. Scores higher than 30 are more specific.A score of 7 for items 1, 6, 9, 12, 15, 18, 19, 22, 24, 27, 30, 34, 38 may indicate Panic Disorder or Significant Somatic Symptoms.A score of 9 for items 5, 7, 14, 21, 23, 28, 33, 35, 37 may indicate Generalized Anxiety Disorder. A score of 5 for items 4, 8, 13, 16, 20, 25, 29, 31 may indicate Separation Anxiety SOC. A score of 8 for items 3, 10, 26, 32, 39, 40, 41 may indicate Social Anxiety Disorder. | Change from SCARED score baseline to 24 months | 
| Children and Adolescent Memory Profile (CHAMP) | 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. This test is administered directly to the participant by a trained examiner. The survey is a comprehensive screen that allows both memory screening and in-depth memory evaluation. The ChAMP includes 4 Subtests (Lists, Objects, Instructions, Places), each with immediate and delayed evaluation modules. Composite scores yielded from this measure include: verbal memory index, visual memory index, immediate memory index, delayed memory index, and total memory index. The ChAMP takes approximately 35 minutes to administer. A score of 3 for items 2, 11, 17, 36 may indicate Significant School Avoidance. | Change from score from baseline to 24 months | 
| DXA Measure of Bone Mineral Density | To assess the axial (central) skeleton, DXA measure of the whole body | Change from baseline bone mineral density to 24 months | 
| DXA Measure of Body Composition | To assess the axial (central) skeleton, DXA measure of the whole body | Change from baseline body composition to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Ovarian Insufficiency, Hormone Replacement Therapy, Estrogen Deficiency