Role of Estrogen on Skeletal Outcomes in FHA

NCT07010146 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 3026821R01HD119174-01
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to assess whether the natural form of estrogen (17-beta estradiol) given as a patch so that it is absorbed through your skin, is better at improving bone strength over 1 year than natural estrogen (17-beta estradiol) taken by mouth, or a synthetic form oestrogen (ethinyl estradiol) given as a patch that also provides birth control. Participants will:

• History and Physical Exams
• Lab Work
• Imaging studies
• Questionnaires
• Dietary recalls

Conditions

Bone Density; Bone Strength; FHA (Functional Hypothalamic Amenorrhea)

Keywords

Estrogen; Functional hypothalamic amenorrhea; Transdermal; Oral

Outcome Measures

Primary Outcomes (4)

• Areal BMD at the spine, hip and femoral neck as well as spine trabecular bone score from DXA

  Using repeated measures analysis, the investigators will compare change in lumbar spine, total hip and femoral neck BMD and trabecular bone score after 12 months of treatment between the transdermal 17β-E2 group and each of the oral 17β-E2 and transdermal EE+LNG groups. BMD and TBS are assessed using DXA. Unit for BMD is g/cm2.

  Baseline and post-treatment (12 months)

• 12-month change in volumetric BMD at the radius and tibia

  Using repeated measures analysis, the investigators will compare change in volumetric BMD at the radius and tibia after 12 months of treatment between the transdermal 17β-E2 group and each of the oral 17β-E2 and transdermal EE+LNG groups. Volumetric BMD is assessed using HRpQCT (mgHA/cm3)

  Baseline and post- treatment (12 months)

• 12-month change in cortical thickness at the radius and tibia

  Using repeated measures analysis, the investigators will compare change in cortical thickness at the radius and tibia after 12 months of treatment between the transdermal 17β-E2 group and each of the oral 17β-E2 and transdermal EE+LNG groups. Cortical thickness is assessed using HRpQCT (mm).

  Baseline and post- treatment (12 months)

• 12-month change in failure load at the radius and tibia

  Using repeated measures analysis, the investigators will compare change in failure load at the radius and tibia after 12 months of treatment between the transdermal 17β-E2 group and each of the oral 17β-E2 and transdermal EE+LNG groups. Failure load is assessed using microfinite element analysis (N).

  Baseline and post- treatment (12 months)

Secondary Outcomes (5)

• 12-month change in IGF-1

  Baseline and post-treatment (12 months)

• 12-month change in SHBG

  Baseline and post-treatment (12 months)

• Associations of 12-month change in IGF-1 with changes in P1NP

  12 months

• Associations of 12-month change in SHBG with changes in P1NP

  12 months

• Associations of 12-month change in P1NP with changes on bone endpoints

  12 monhts

Study Arms (3)

transdermal 17β-E2 with cyclic progestin

EXPERIMENTAL

Drug: transdermal 17β-E2 with cyclic progestin

oral 17β-E2 with cyclic progestin

EXPERIMENTAL

Drug: oral 17β-E2 with cyclic progestin

transdermal EE+LNG

EXPERIMENTAL

Drug: transdermal EE+LNG

Interventions

transdermal 17β-E2 with cyclic progestin DRUG

100-mcg transdermal 17β-E2 patch (to be applied twice weekly) (continuous use), with 200 mg micronized progesterone given for 12 days of every month

transdermal 17β-E2 with cyclic progestin

oral 17β-E2 with cyclic progestin DRUG

2 mg of oral 17β-E2 pills daily, with 200 mg micronized progesterone given for 12 days of every month

oral 17β-E2 with cyclic progestin

transdermal EE+LNG DRUG

transdermal EE (30 mcg) + LNG (120 mcg) contraceptive patch (TWIRLA). Patch will be applied once a week for 3 consecutive weeks, with the 4th week off the patch (to be repeated after 4 weeks).

transdermal EE+LNG

Eligibility Criteria

• Age: 14 Years - 30 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Females, age 14-30 years, skeletally mature with bone age ≥ 14 years (only 2% of growth left)
• Women of reproductive age: use of an effective non-hormonal contraceptive method or a progestin releasing intrauterine device (no systemic skeletal effects) for study duration if sexually active. Note: Women who receive a progestin implant for contraception after study enrollment will be allowed to continue and will not be excluded from study.
• Biochemical criteria: negative βHCG (pregnancy test), TSH within 2x the upper limit of normal, prolactin \<10 ng/mL above upper limit of normal, potassium between 3.0-5.0, ALT ≤3 times upper limit of normal, LDL ≤190 mg/dl.
• Patients with known hypothyroidism will be included if appropriately treated with levothyroxine and have a TSH within 2x the upper limit of normal for at least a month preceding the baseline study visit.
• Menstrual criteria: \< 3 menses in the preceding 6 months.

You may not qualify if:

• Disease other than FHA known to affect bone, including untreated thyroid dysfunction, Cushing's disease, renal failure, diabetes mellitus
• Primary thyroid dysfunction will be defined as a TSH level more than 2X the upper limit of normal per given reference range with unknown thyroid antibody status, or an abnormal TSH if known positive antibodies.
• Patients with hypothyroidism will be excluded if not appropriately treated with levothyroxine and if they do not have a TSH level within 2X the upper limit of normal for at least a month preceding the baseline study visit, given possible effects on the reproductive axis and bone.
• Use of other medications known to affect bone metabolism within 3 months of the study (other than calcium and vitamin D supplementation)
• Substance use disorder; current smoker (\>10 cigarettes per day)
• Pregnant, planning to become pregnant within 12 months of the end of treatment and/or breastfeeding
• Hypertension or use of anti-hypertensive medications
• Other conditions causing oligo-amenorrhea such as PCOS, premature ovarian insufficiency
• Known sensitivity or absolute contraindication to any component of study medications (high risk thromboembolic disease, breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors, acute viral hepatitis, decompensated cirrhosis, undiagnosed abnormal uterine bleeding
• BMI ≥ 25 kg/m2 (efficacy of the contraceptive patch being used in the study is lower at higher BMIs)

Sponsors & Collaborators

• University of Virginia: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (2)

University of Virginia Medical Center

Charlottesville, Virginia, 22903, United States

RECRUITING

University of Virginia

Charlottesville, Virginia, 22908, United States

RECRUITING

Study Officials

• Madhusmita Misra, MD, MPH

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Madhusmita Misra, MD, MPH

CONTACT

434-924-9141; madhusmita.misra@uvahealth.org

Sara Braslow, BA

CONTACT

434-982-4234; EVZ3BW@uvahealth.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: May 30, 2025
• First Posted: June 8, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): May 31, 2030
• Last Updated: July 17, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ICF
• Time Frame: Data sharing will occur no later than the end of performance period of the extramural award that generated the data. There is no end date planned at this time.
• Access Criteria: Study investigators will make access to deidentified data available via repository without restriction to access. Data available will include deidentified demographic data and those related to primary and secondary endpoints.

Locations

US (2)