Transdermal Estrogen for Anorexia Nervosa

Overseen By Pouneh Fazeli, MD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Trial Phase: Phase 2

Sponsor: Pouneh K. Fazeli, MD

Must not be taking: Glucocorticoids, Bisphosphonates

Disqualifiers: Thyroid dysfunction, Diabetes, Breast cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

66 Participants Needed

Trial Summary

What is the purpose of this trial?

Randomized, placebo-controlled study investigating the use of physiologic, transdermal estrogen for low bone mass in adult women with anorexia nervosa.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications known to affect bone metabolism, such as certain steroids or bisphosphonates, for specific periods before starting the trial. If you're on these medications, you may need to stop them for a while before participating.

What data supports the effectiveness of the transdermal estrogen treatment for anorexia nervosa?

A study found that using transdermal estrogen for 6 months increased bone mineral density (BMD) in the spine of women with anorexia nervosa, suggesting it may help improve bone health in these patients. ^{1 2 3 4 5}

Is transdermal estrogen safe for use in humans?

Transdermal estrogen, often used in patches, is generally well-tolerated with the most common side effect being mild skin irritation at the application site. It avoids certain liver-related side effects seen with oral estrogen and has not shown adverse biochemical changes in studies, though there is a noted increased risk of breast cancer with long-term use in postmenopausal women. ^{6 7 8 9 10}

How is the transdermal estrogen patch unique for treating anorexia nervosa?

The transdermal estrogen patch is unique because it delivers estrogen through the skin, bypassing the liver, which can reduce certain side effects associated with oral estrogen. This method is convenient with a once-weekly application and may improve long-term treatment adherence. ^{7 8 11 12 13}

Research Team

Pouneh Fazeli, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for adult women aged 19-45 with anorexia nervosa, specifically those who are underweight according to specific tables and have low bone mass. Participants must not be pregnant or planning pregnancy soon, should not have a history of certain blood or bone disorders, no recent use of medications affecting bone metabolism, and no severe illnesses like diabetes or untreated thyroid issues.

Inclusion Criteria

<85% of ideal body weight as defined by the 1983 Metropolitan Life Insurance Height and Weight Tables

The T-score of your bone scan is less than -1.0 at spine or hip.

I have been diagnosed with anorexia nervosa.

Exclusion Criteria

I or my close family member had breast cancer.

25-OH vitamin D level < 20 ng/mL

Pregnant or breastfeeding (or desiring pregnancy within the next 18 months)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a transdermal estrogen/progesterone patch or a placebo patch applied weekly for 18 months

18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Transdermal estrogen

Trial Overview The study is testing the effects of transdermal estrogen patches compared to placebo on improving bone density in women with anorexia nervosa. It's a randomized trial meaning participants will be randomly assigned to either the treatment group receiving estrogen or the control group receiving a placebo.

Participant Groups

Group I: Transdermal estrogen/progesterone Experimental Treatment 1 Intervention

Transdermal estradiol (0.045mg)/levonorgestrel (0.015mg) patch applied weekly for 18 months

Group II: Placebo Placebo Group 1 Intervention

Placebo patch applied weekly for 18 months

Transdermal estrogen is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Estradiol patch for:

• Menopause symptoms
• Osteoporosis prevention
• Hormone replacement therapy

Approved in European Union as Estradiol patch for:

• Menopause symptoms
• Osteoporosis prevention
• Hormone replacement therapy

Approved in Canada as Estradiol patch for:

• Menopause symptoms
• Osteoporosis prevention
• Hormone replacement therapy

Who Is Running the Clinical Trial?

Pouneh K. Fazeli, MD

Lead Sponsor

Trials

1

Recruited

70+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

In a 6-month study involving 11 women with anorexia nervosa, treatment with transdermal estradiol and levonorgestrel resulted in significant increases in bone mineral density (BMD) at the lumbar spine, indicating potential benefits for bone health in this population.

The treatment also led to a significant decrease in bone marrow adipose tissue (BMAT) after 3 months, suggesting that physiologic doses of estrogen may help improve bone quality in women with anorexia nervosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal Estrogen in Women With Anorexia Nervosa: An Exploratory Pilot Study. Resulaj, M., Polineni, S., Meenaghan, E., et al.[2020]

Estrogen preparations (EP) have a moderate positive effect on bone mineral density in the lumbar spine of women with anorexia nervosa, but no significant effect on the femoral neck, based on a systematic review of two cohort studies and four randomized clinical trials.

The evidence regarding the benefits of EPs is low quality, and they should generally be avoided in women with anorexia nervosa, especially when the focus is on achieving weight and nutritional rehabilitation rather than just resuming menstrual cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses. Sim, LA., McGovern, L., Elamin, MB., et al.[2018]

In a study of 13 patients with anorexia nervosa, significant hormonal deficiencies were observed, with estradiol, LH, and FSH levels markedly lower than those in a control group, indicating a disruption in reproductive hormone regulation due to the condition.

Administration of LH-RH resulted in a significant increase in LH and FSH levels, suggesting that hormonal response mechanisms are still functional in these patients, which could have implications for treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The adenohypophyseal gonadotropins in patients with anorexia nervosa]. Smiljanić, N., Ciglar, S., Kasnar, V., et al.[2015]

In a study involving 70 adolescent girls with anorexia nervosa, treatment with DHEA combined with estrogen/progestin for 12 months significantly reduced bone marrow fat in the distal femur compared to a placebo, indicating a potential to prevent bone loss.

The treatment was particularly effective in girls with a body mass index (BMI) above 18 kg/m², suggesting that higher BMI may enhance the therapeutic benefits of DHEA and hormone therapy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging and spectroscopy evidence of efficacy for adrenal and gonadal hormone replacement therapy in anorexia nervosa. Vajapeyam, S., Ecklund, K., Mulkern, RV., et al.[2020]

In a 12-month study involving 70 adolescent girls with anorexia nervosa, the combination of DHEA and estrogen replacement therapy did not significantly improve bone mineral density compared to a placebo.

Among participants with open growth plates, those receiving DHEA + estrogen actually experienced a greater decline in bone density than those on placebo, indicating that this treatment may be ineffective for preserving bone health in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Adrenal Hormone Supplementation on Bone Geometry in Growing Teens With Anorexia Nervosa. DiVasta, AD., Feldman, HA., O'Donnell, JM., et al.[2021]

The estradiol transdermal therapeutic system effectively delivers estradiol to maintain premenopausal levels in postmenopausal women, helping to protect against osteoporosis and reduce fracture risk with minimal dosages.

This method of delivery is well-tolerated, with local irritation being the most common side effect, and it offers similar benefits for menopausal symptoms as oral estrogens, making it a promising alternative for estrogen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis. Balfour, JA., McTavish, D.[2018]

The Estraderm Transdermal System, which delivers 17-beta estradiol, is an effective method for estrogen replacement therapy, providing relief from climacteric symptoms similar to oral estrogens, with localized skin irritation as the primary side effect in about 15% of users.

Transdermal estrogen therapy may have advantages over oral estrogen, such as bypassing the liver to reduce risks associated with blood pressure elevation, but there are concerns about an increased risk of breast cancer, highlighting the need for further long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen replacement therapy and the estraderm transdermal system. Youngkin, EQ.[2013]

The transdermal therapeutic system of estrogen (Estraderm) is effective in relieving hot flushes and vaginal atrophy, showing similar efficacy to oral estrogen treatments while maintaining bone health.

The patch is well tolerated with minimal side effects, such as low incidence of endometrial hyperplasia and breast tenderness, and patients generally prefer this method over oral administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with transdermal estradiol in the treatment of the climacteric. Utian, WH.[2013]

The transdermal therapeutic system for estrogen administration (Estraderm) is effective and well tolerated, showing no adverse effects on liver proteins compared to oral conjugated estrogens, based on both single- and multicenter clinical studies.

While moderate bleeding occurred in some patients, it can be managed with progestogen, and the overall incidence of serious side effects like endometrial hyperplasia and breast tenderness is low, with patients generally preferring the transdermal method over oral administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal estradiol overall safety profile. Utian, WH.[2019]

In a study of 296 transgender individuals on feminizing hormone therapy, those aged 45 and older were more likely to be treated with transdermal estradiol, which is recommended for this age group due to potential cardiovascular risks.

Despite similar serum estradiol levels between age groups, older individuals receiving oral estradiol were prescribed lower doses, highlighting the need for tailored cardiovascular risk management in aging transgender populations, especially given the high prevalence of conditions like hypertension and obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feminizing Hormone Therapy Prescription Patterns and Cardiovascular Risk Factors in Aging Transgender Individuals in Australia. Balcerek, MI., Nolan, BJ., Brownhill, A., et al.[2021]

The new estradiol transdermal patch, applied once weekly, effectively increased plasma estradiol levels in postmenopausal women, achieving average concentrations proportional to the patch strength (25, 50, and 75 micrograms/day) over a 7-day period.

The patches were well tolerated with only mild and transient skin reactions, and they showed good systemic tolerability, making them a practical option for long-term estrogen replacement therapy to manage postmenopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol and estrone plasma levels during application of three strengths of a 7-day estradiol transdermal patch. Setnikar, I., Rovati, LC., Santoro, A., et al.[2013]

In a study of 104 postmenopausal women, the Systen estradiol patch was found to have better tolerability and adhesion compared to the Estraderm patch, with 79% of Systen users rating their treatment as 'good' or 'very good'.

Overall satisfaction with therapy was higher for Systen (53%) compared to Estraderm (46%), indicating that Systen may be a more effective option for estrogen replacement therapy in terms of patient acceptance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. Van Leusden, HA., Albertyn, G., Verlaine, C., et al.[2013]

In a 96-week study involving 124 postmenopausal women, the transdermal patch containing estradiol/norethisterone acetate (E(2)/NETA) significantly increased bone mineral density (BMD) at the lumbar spine compared to placebo, indicating its efficacy in reducing bone loss.

The E(2)/NETA patch not only prevented bone loss but also reduced the frequency of bone remodeling, showing effects on the hip similar to those seen with higher doses of estrogen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women. Rubinacci, A., Peruzzi, E., Modena, AB., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Transdermal Estrogen in Women With Anorexia Nervosa: An Exploratory Pilot Study. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses. [2018]

3. Croatia pubmed.ncbi.nlm.nih.gov

[The adenohypophyseal gonadotropins in patients with anorexia nervosa]. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging and spectroscopy evidence of efficacy for adrenal and gonadal hormone replacement therapy in anorexia nervosa. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Impact of Adrenal Hormone Supplementation on Bone Geometry in Growing Teens With Anorexia Nervosa. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Estrogen replacement therapy and the estraderm transdermal system. [2013]

8. Italy pubmed.ncbi.nlm.nih.gov

Clinical experience with transdermal estradiol in the treatment of the climacteric. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Transdermal estradiol overall safety profile. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Feminizing Hormone Therapy Prescription Patterns and Cardiovascular Risk Factors in Aging Transgender Individuals in Australia. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Estradiol and estrone plasma levels during application of three strengths of a 7-day estradiol transdermal patch. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. [2013]

13. United States pubmed.ncbi.nlm.nih.gov

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women. [2019]