Recruiting
Phase 2

17-Beta Estradiol, Ethinyl Estradiol

Sponsor:

University of Virginia

Code:

NCT07010146

Conditions

Bone Strength

Bone Density

FHA (Functional Hypothalamic Amenorrhea)

Eligibility Criteria

Sex: Female

Age: 14 - 30

Healthy Volunteers: Not accepted

Interventions

transdermal 17β-E2 with cyclic progestin

oral 17β-E2 with cyclic progestin

transdermal EE+LNG

Study Details

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:

1. Take estrogen for 1 year either (i) in its natural form as a patch twice a week (and progesterone by mouth for 12 days of each month), or (ii) in its natural form as a pill daily (and progesterone by mouth for 12 days of each month), or (iii) in a synthetic form as a birth control patch weekly for 3 weeks with 1 week off the patch. You will not be able to choose which form of estrogen you will receive as this will be assigned to you based on a pre-existing randomization sequence (like the flip of a coin)
2. Take provided calcium and vitamin D supplements
3. Attend 4 study visits over 12 months with two at the beginning and then every 6 months that include:

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

Conditions

Bone Strength

Bone Density

FHA (Functional Hypothalamic Amenorrhea)

Study ID

NCT07010146

Start date

Oct 1, 2025

Status verified date

Jul, 2026

Completion date

May 31, 2030

Anticipated

Primary completion date

Dec 31, 2029

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: Female

Age: 14 - 30

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • Disease other than FHA known to affect bone, including untreated thyroid dysfunction, Cushing's disease, renal failure, diabetes mellitus

1. 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.
2. 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)

Study Design

Enrollment

150 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: transdermal 17β-E2 with cyclic progestin

experimental: oral 17β-E2 with cyclic progestin

experimental: transdermal EE+LNG

Interventions

transdermal 17β-E2 with cyclic progestin

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

oral 17β-E2 with cyclic progestin

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

transdermal EE+LNG

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).

Primary outcome measure

  • Areal BMD at the spine, hip and femoral neck as well as spine trabecular bone score from DXA [ Time Frame: Baseline and post-treatment (12 months) ]
  • 12-month change in volumetric BMD at the radius and tibia [ Time Frame: Baseline and post- treatment (12 months) ]
  • 12-month change in cortical thickness at the radius and tibia [ Time Frame: Baseline and post- treatment (12 months) ]
  • 12-month change in failure load at the radius and tibia [ Time Frame: Baseline and post- treatment (12 months) ]

Central Contacts and Locations

Central contacts

Madhusmita Misra, MD, MPH

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

Sara Braslow, BA

434-982-4234EVZ3BW@uvahealth.edu

Locations

University of Virginia Medical Center

Recruiting

Charlottesville, Virginia, United States, 22903

Contacts

Madhusmita Misra, MD, MPH

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

cmb6w@virginia.edu

Principal Investigator:

Madhusmita Misra, MD, MPH

University of Virginia

Recruiting

Charlottesville, Virginia, United States, 22908

Contacts

Madhusmita Misra

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

More Information

Sponsor

University of Virginia

Last update posted

Jul 17, 2026

Last verified

Jul, 2026

Keywords

  • Estrogen
  • Functional hypothalamic amenorrhea
  • Transdermal
  • Oral

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by University of Virginia on 2026-07-17.