Hormone Replacement Therapy in Adolescents With Premature Ovarian Insufficiency

Overview

Background: Premature ovarian insufficiency (POI) is a condition in which women under the age of 40 years have absent or irregular menstrual cycles. POI can cause infertility, signs of menopause, osteoporosis, and other symptoms. Hormone replacement therapy (HRT) is a treatment that gives women extra hormones, such as estrogen and progesterone. HRT works well in adult women. Researchers want to find the most effective doses and regimens for adolescents. Objective: To monitor the effects of HRT on adolescents with POI. Eligibility: Female adolescents aged 11 to 19 years diagnosed with POI. Healthy volunteers are also needed. Design: All participants will have clinic visits every 6 months for 2 years. Each visit may last 2 days. Each visit may include: Blood and urine tests. A test of their heart function. A test to measure the stiffness of their blood vessels. Participants will lie flat with a blood pressure cuff on a leg and a meter on the neck while the cuff inflates. A test of their grip strength. Participants will squeeze a handheld device as hard as they can. Two scans to measure bone density. For one, participants will lie on a table while a scanner passes along their body. For the other, participants will sit in a chair and insert their forearm, then their lower leg, into a scanner. A test to measure skin pigmentation. Participants' skin will be touched lightly with a device. An optional visual exam of the vagina. Some vaginal fluid may also be collected with a cotton swab/cytobrush. Participants with POI will receive HRT. They will be given estrogen patches and progesterone pills.

Detailed description

Study Description:

This is a study of adolescents with premature ovarian insufficiency (POI) and their response to hormone replacement therapy (HRT).

Objectives:

Primary:

To identify the phenotype and associated genotype of adolescents with POI at the time of diagnosis, including assessment of overall bone health of participants pre- and post-HRT treatment with respect to bone mineral density (BMD) and other skeletal endpoints.

Bone Health:

-Follow patients with POI for bone health assessments:

* Measure BMD at different skeletal sites, including the central skeleton (lumbar spine, total body less head, and hip - femoral neck and total hip) * Perform vertebral fracture assessment (VFA) * Determine body composition of lean body and fat mass (total body) and correlate with BMD. * Assess skin pigmentation and muscle grip strength and correlate with BMD

Secondary:

Bone Health

-Follow patients with POI for bone health assessments:

* Measure BMD at peripheral skeleton (radius and tibia) * Evaluate bone microarchitecture and strength of the radius and tibia.

Metabolic Phenotype:

* Follow patients with POI for metabolic assessment:

* Insulin resistance * Cardiovascular risk * Lipid profiles * Bone turnover

Muscle Phenotype:

-Follow patients with POI for muscle function assessment:

* Determine hand grip muscle strength * Evaluate lean body mass (by DXA) to determine muscle mass

Cardiovascular Health

-Follow patients with POI for a cardiovascular evaluation:

* Electrophysiologic parameters (from 12-lead EKG) * Arterial stiffness (by Pulse Wave Velocity, PWV) * Coagulation studies to determine the impact of HRT on clotting function

Genetic profiling:

-If obtained, assess the baseline genotype of patients with POI to correlate with BMD and other health outcomes

--If subjects are co-enrolled on NIAID protocol 17I0122, utilize that genetic sequencing data to associate with genotype and response of multiple health outcomes to HRT.

Quality of Life:

-Follow patients with POI for evaluation of an individual s perception of their life quality and health:

* Evaluate the individual s perceived occupational performance in self-care, productivity, and leisure * Evaluate the individual s occupations or hobbies that align with their interests

Psychological health:

-Follow patients with POI for evaluation of an individual s mood and well-being:

* Measure symptoms and severity of depression * Measure the state and trait components of anxiety

Menopause profile:

-Follow patients with POI for determining signs and symptoms of menopause:

* Evaluate reproductive hormonal changes * Assess menopausal symptoms and their severity * Evaluate vaginal health

Hormone Replacement Therapy:

-Follow patients with POI longitudinally to determine the most effective HRT management:

* Evaluate dosage, delivery, combination of HRT * Evaluate effects of HRT on bone, cardiovascular, metabolic, gynecologic, and psychological health

Endpoints:

Primary:

Longitudinal evaluation of BMD of the central skeleton (lumbar spine).

As secondary measures of bone health, dual-energy x-ray absorptiometry (DXA) measures of skeletal sites other than the spine (DXA - hip/total body) will be evaluated longitudinally in POI participants and their BMD compared to healthy control participants. Using DXA, vertebral fractures assessment (VFA) will be performed in POI participants and compared to healthy control participants. In addition, BMD will be evaluated with respect to skin pigmentation and muscle grip strength.

Interventions

• Drug Progesterone
  Oral micronized progesterone will be added (100 mg/day for 12 days/month) in the event of spontaneous vaginal bleeding and/or at 12 months over the 2-year protocol.
• Drug Estrogen Patch
  participants with POI (n=85) will receive transdermal 17 beta-estradiol (beginning at a dose of 25 microgram/patch applied weekly), with the dose increased at 3 months to 50 microgram, and thereafter every 6 months to 75 and 100 microgram/patch for pubertal induction or estrogen replacement (with 100 microgram/patch representing a full adolescent or young adult estradiol dose). The continued escalation of the estradiol dose and patch strength will be guided by the clinical presentation and physi

Primary outcome measures

• Longitudinal evaluation of BMD of the central skeleton (lumbar spine). [Time frame: 2 years]

Secondary outcome measures (9)

• Evaluate bone density and strength of the radius and tibia in participants with POI and compare with healthy controls. [Time frame: 2 years]
• Compare metabolic and cardiovascular parameters between participants with POI and healthy controls. [Time frame: 2 years]
• Assess muscle strength and lean body mass in participants with POI compared to healthy controls. [Time frame: 2 years]
• Analyze heart repolarization, arterial stiffness, and coagulation parameters in participants with POI versus healthy controls. [Time frame: 2 years]
• Compare the genetic background of participants with POI to healthy controls using whole genome sequencing. [Time frame: 2 years]
• Assess quality of life using COPM and Interest Checklist questionnaires. [Time frame: 2 years]
• Evaluate psychological health using the Beck Depression Inventory and Spielberger State/Trait Anxiety Inventory. [Time frame: 2 years]
• Compare menopausal profile, including ovarian hormone levels and responses to the Menopause Rating Scale, between participants with POI and healthy controls. [Time frame: 2 years]
• Assess health effects of a typical clinical HRT regimen over two years. [Time frame: 2 years]

Eligibility criteria

• INCLUSION CRITERIA:

Inclusion Criteria for POI Participants

To be eligible to participate in this study, an individual must meet all the following criteria:

• Individuals aged 11-19 years, inclusive, at the time of enrollment.
• Diagnosis of premature ovarian insufficiency.
• Documentation of one elevated serum FSH measurement greater than the testing laboratory's upper reference range (for age/Tanner stage).
• Identify as female (i.e., sex assigned at birth)
• Negative pregnancy test.

Inclusion Criteria for Healthy Volunteers:

• Individuals aged 11-19 years.
• Identify as female (i.e., sex assigned at birth)
• Negative pregnancy test.
• Absence of known chronic disease

Exclusion criteria

Male participants are excluded from both study groups (POI and Healthy Volunteers) as POI affects only the female reproductive system, while pregnant participants are not eligible to have DXA or HRpQCT imaging for safety reasons.

Exclusion Criteria for POI participants:

An individual who meets any of the following criteria will be excluded from participation in this study:

• POI in the setting of Turner syndrome.
• Patients who screened positive for celiac disease.
• Receipt of any medications including HRT determined by the investigator to affect bone metabolism 3 months prior to enrollment.
• Any medical condition determined by the investigator to affect bone health will be excluded.
• Presence of a medical, psychiatric, or social condition which, in the opinion of the investigator, would place undue burden on the subject, NIH resources, or increase risk of participation.
• Report of sexual activity but refusal to use a copper intrauterine device or double barrier forms of contraception during the study.

Exclusion Criteria for Healthy Volunteers:

For healthy volunteers, all exclusion criteria will apply as for POI participants except for number 1.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Identifiers

NCT: NCT06851754 · 10002141 · 002141-CH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗