Which form of estrogen best improves bone strength in women with functional hypothalamic amenorrhea?

Role of Estrogen Formulation and Route of Delivery on Skeletal Outcomes in Functional Hypothalmic Amenorrhea

This trial will test whether natural estrogen patches, natural estrogen pills, or a birth-control estrogen patch better improve bone strength over one year in adolescents and young women with functional hypothalamic amenorrhea.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 150 (estimated)
• Ages: 14 Years to 30 Years
• Sex: Female
• Sponsor: University of Virginia (other)
• Locations: 2 sites (Charlottesville, Virginia and 1 other locations)
• Trial ID: NCT07010146 on ClinicalTrials.gov

What this trial studies

Adolescents and young adult females with functional hypothalamic amenorrhea will be randomly assigned to one of three estrogen regimens for 12 months: transdermal 17-beta estradiol patches with cyclic oral progesterone, oral 17-beta estradiol with cyclic oral progesterone, or a transdermal ethinyl estradiol-plus-levonorgestrel birth-control patch. All participants receive provided calcium and vitamin D supplements and attend four study visits over the year with bone density and strength measurements at baseline and follow-up. The trial directly compares natural estradiol delivered through the skin versus by mouth and versus a synthetic contraceptive patch to see which approach better preserves or improves skeletal health during the critical bone-accrual years.

Who should consider this trial

Good fit: Females aged 14–30 who are skeletally mature with fewer than three menses in the prior six months and who can use non-hormonal contraception or an eligible intrauterine device if sexually active would be ideal candidates.

Not a fit: People with other medical causes of low bone mass or amenorrhea, contraindications to estrogen therapy, pregnancy, or who cannot attend study visits at the trial site are unlikely to benefit from enrolling.

Why it matters

Potential benefit: If successful, the findings could identify an estrogen approach that better preserves bone mass and lowers future fracture risk in young women with FHA.

How similar studies have performed: Previous research indicates combined oral contraceptive pills do not improve bone in FHA, while smaller studies suggest transdermal estradiol may help but definitive randomized results are lacking.

Eligibility criteria

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)

Where this trial is running

Charlottesville, Virginia and 1 other locations

• University of Virginia Medical Center — Charlottesville, Virginia, United States (RECRUITING)
• University of Virginia — Charlottesville, Virginia, United States (RECRUITING)

Study contacts

• Principal investigator: Madhusmita Misra, MD, MPH — University of Virginia
• Study coordinator: Madhusmita Misra, MD, MPH

Conditions: Bone Strength, Bone Density, FHA, Estrogen, Functional hypothalamic amenorrhea, Transdermal, Oral