Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

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: Primary Ovarian Insufficiency
• Intervention / Treatment: Drug: Transdermal Estrogen

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

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 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 glucocorticords, 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 SSRIs, antipsychotics or have any documented problems with anxiety or depression.
5. Be currently pregnant (as confirmed by pregnancy testing)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

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
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

Collaborators and Investigators

• 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

General Publications

• Gordon CM, Kanaoka T, Nelson LM. Update on primary ovarian insufficiency in adolescents. Curr Opin Pediatr. 2015 Aug;27(4):511-9. doi: 10.1097/MOP.0000000000000236.
• Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009 Feb 5;360(6):606-14. doi: 10.1056/NEJMcp0808697.
• Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014 Jul;124(1):193-197. doi: 10.1097/01.AOG.0000451757.51964.98.
• Sadeghi MR. New hopes for the treatment of primary ovarian insufficiency/premature ovarian failure. J Reprod Infertil. 2013 Jan;14(1):1-2. No abstract available.
• Gordon CM, Zemel BS, Wren TA, Leonard MB, Bachrach LK, Rauch F, Gilsanz V, Rosen CJ, Winer KK. The Determinants of Peak Bone Mass. J Pediatr. 2017 Jan;180:261-269. doi: 10.1016/j.jpeds.2016.09.056. Epub 2016 Nov 3. No abstract available.
• Bakhsh H, Dei M, Bucciantini S, Balzi D, Bruni V. Premature ovarian insufficiency in young girls: repercussions on uterine volume and bone mineral density. Gynecol Endocrinol. 2015 Jan;31(1):65-9. doi: 10.3109/09513590.2014.958987. Epub 2014 Sep 9.
• Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, Troendle JF, Nelson LM. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009 Jul;94(7):2277-83. doi: 10.1210/jc.2008-1878. Epub 2009 Apr 28.

Study record dates

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 (Estimate): January 16, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Primary Ovarian Insufficiency; Hormone Replacement Therapy; Estrogen Deficiency
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Primary Ovarian Insufficiency; Menopause, Premature; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Estrogens
• 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