Estradiol Products for Menopause

Overseen By Audra Stinchcomb, PhD

Age: 18+

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Estrogens, Antihistamines, Corticosteroids, others

Disqualifiers: Smoking, Skin disorders, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two estradiol treatments to determine if they deliver similar amounts of the hormone estradiol, which can help manage menopause symptoms. Participants will use either a compounded estradiol product or Divigel, both applied as gels. The trial is open to postmenopausal women who have been without periods for at least a year and do not have complicating health conditions such as diabetes or a history of blood clots. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires participants to stop using medications for menopausal symptoms and certain other medications within 30 days before the study. However, some medications like thyroid medications, non-steroidal anti-inflammatory drugs, and cholesterol-lowering drugs are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Divigel 0.1%, a type of estradiol gel, is approved for treating menopause symptoms. However, it carries serious warnings. Divigel use can increase the risk of blood clots, heart attack, stroke, and certain cancers, such as breast and uterine cancer. Additionally, there is a higher risk of dementia, particularly if treatment begins after age 65.

In contrast, compounded estradiol products are custom-made for individuals and lack the same safety warnings as FDA-approved hormone therapies, making their safety less certain. There is insufficient high-quality information about the safety and effectiveness of these compounded products for menopause symptoms.

In an early phase trial like this one, the primary goal is to gather more information about safety and how well participants tolerate the treatment. Since Divigel is an approved product, its safety profile is better understood. However, the safety of compounded estradiol remains unclear, so staying informed and discussing any concerns with healthcare providers is crucial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for menopause symptoms involve hormone replacement therapy using standard estradiol products like oral tablets or patches. However, researchers are excited about the compounded estradiol gel and Estrogel 0.06% because they offer a topical application method, which may reduce systemic side effects compared to oral administration. This method allows the hormone to be absorbed directly through the skin, potentially leading to more stable hormone levels and fewer fluctuations. Additionally, using a compounded product equivalent to Divigel provides a customizable option for patients who may need specific dosing not available in standard formulations.

What evidence suggests that this trial's treatments could be effective for menopause?

This trial will compare Divigel® (estradiol gel) 0.1% with a compounded estradiol product. Studies have shown that Divigel® effectively treats moderate to severe hot flashes in menopausal women. The FDA has approved it, and it has successfully reduced these symptoms. In contrast, custom-made estradiol products, like the compounded estradiol product in this trial, lack strong evidence supporting their effectiveness. Some research suggests these custom products might not provide consistent estrogen levels compared to FDA-approved options. The effectiveness of these custom products can vary, leading to less confidence in their results. ^{2 4 6 7 8}

Who Is on the Research Team?

Audra Stinchcomb, PhD

Principal Investigator

University of Maryland, Baltimore

Are You a Good Fit for This Trial?

This trial is for postmenopausal women aged 45-65 with healthy organ function and no drug abuse history. Participants must have legs long enough to apply the gel over a specific area and be comfortable with it. They should not be on any medication that could affect the study outcome.

Inclusion Criteria

Have normal screening laboratories for urine protein and urine glucose

Able to adhere to the study restrictions and study schedule

Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, benzodiazepine, cocaine, methadone, opiates, PCP)

Exclusion Criteria

Participation in any ongoing clinical drug trial/study

Positive urine drug screening test

I have not donated or lost more than one pint of blood in the last 60 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Divigel 0.1% or a compounded estradiol product to evaluate serum concentrations over four consecutive days

1 week

Daily visits for 4 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Compounded estradiol gel
• Estradiol
• Estrogel 0.06 % Topical Gel

Trial Overview The trial is testing two types of estradiol gels: Estrogel and a compounded version, to see if they deliver similar amounts of hormone after being applied once or multiple times.

How Is the Trial Designed?

Group I: Divigel 0.1% Active Control 1 Intervention

Divigel 0.1% (1.25 g of gel/dose)

Group II: Compounded estradiol product Active Control 1 Intervention

Compounded estradiol product (equivalent to Divigel/dose)

Compounded estradiol gel is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis
• Palliation therapy for breast cancer
• Palliation therapy for androgen-dependent prostate cancer

Approved in Canada as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis

Approved in European Union as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Published Research Related to This Trial

Divigel 1.0 mg was found to be the most effective treatment for reducing hot flush frequency in postmenopausal women, significantly outperforming all other estradiol gel doses, including Estrogel 1.5 mg, which had the least efficacy.

While Divigel 1.0 mg showed the best efficacy, it also had a higher risk of treatment-related adverse events compared to placebo, indicating a trade-off between effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis. Derzko, C., Sergerie, M., Siliman, G., et al.[2018]

Oesclim, a new estradiol transdermal delivery system, demonstrated comparable pharmacokinetics to Vivelle 0.05 in delivering estradiol, with similar absorption rates and maximum serum concentrations in a study of 24 postmenopausal women.

Oesclim 50 showed better skin tolerance and adhesion compared to Vivelle 0.05, with no reports of skin intolerance for Oesclim 50, while skin issues were more common with the higher dose Oesclim 100 and Vivelle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the pharmacokinetics of 17 beta-estradiol after a single 4-day application of Oesclim 50, Oesclim 100, and Vivelle 0.05 (Menorest 50) transdermal delivery systems. Guichard, JP., Sauron, R., Jones, AB.[2019]

The 7-day estradiol transdermal patch (Climara) effectively reduces hot flushes in women, with a mean decline of 74.6% for the higher dose compared to 64.5% for the lower dose, showing comparable efficacy to traditional hormone therapies.

The Climara patch is well tolerated, with a low withdrawal rate due to adverse events (8.9%), primarily related to skin reactions, and it demonstrated better adhesion compared to other patches, making it a practical option for estrogen replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy. Gordon, SF.[2019]

In a 12-week study involving 273 postmenopausal women, the estradiol transdermal delivery system significantly reduced the frequency of moderate-to-severe hot flushes compared to placebo, with effects noticeable as early as 2 weeks for the 100-microgram/d dose and 3 weeks for the 50-microgram/d dose.

While the treatment was effective, there were some estrogen-related side effects, such as breast pain and breakthrough bleeding, which were more common in the active treatment groups than in the placebo group, indicating a need for monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Alora Study Group. Good, WR., John, VA., Ramirez, M., et al.[2019]

In a 12-month study involving 395 postmenopausal women, transdermal estradiol gel combined with either monthly or quarterly oral progestogen effectively reduced climacteric symptoms like hot flushes and vaginal dryness, with over 87% of participants completing the study.

Both treatment regimens showed similar bleeding patterns and endometrial safety, with only 0.3% of women experiencing endometrial hyperplasia, and 97% of participants found the gel to be acceptable or convenient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding. Hirvonen, E., Crona, N., Wahlström, T., et al.[2019]

In a 12-week study involving 488 postmenopausal women, estradiol gel 0.1% significantly reduced the frequency and severity of vasomotor symptoms, showing effects as early as Week 2 compared to placebo.

All three doses of estradiol gel 0.1% also improved signs of vulvar and vaginal atrophy, making it an effective treatment option with flexible dosing for managing menopause symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women. Hedrick, RE., Ackerman, RT., Koltun, WD., et al.[2013]

In a study of 425 women undergoing in vitro fertilization, transdermal estradiol hemihydrate (Divigel) resulted in a comparable increase in endometrial thickness to oral estradiol valerate, while requiring significantly lower doses and shorter treatment duration.

Both treatment groups had similar pregnancy and 'take home baby' rates, indicating that transdermal estrogens are effective for improving endometrial conditions without increasing the total estrogen exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thin endometrium problem in IVF programs. Vartanyan, E., Tsaturova, K., Devyatova, E.[2021]

Estradiol gel 0.1% significantly reduced the frequency and severity of moderate to severe vasomotor symptoms in postmenopausal women, regardless of their age, uterine status, or ovarian status, based on a reanalysis of a phase III clinical trial.

The study found no interactions between the treatment and factors like age or surgical history, indicating that estradiol gel is effective across different demographics of postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol gel 0.1% relieves vasomotor symptoms independent of age, ovarian status, or uterine status. Hedrick, RE., Ackerman, RT., Koltun, WD., et al.[2013]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK562865/

The Safety and Effectiveness of Compounded Bioidentical ... The estradiol product appeared more effective ... Other studies suggest compounded testosterone may be effective in treating vaginal atrophy and other menopausal ...

2. acog.org acog.org/clinical/clinical-guidance/clinical-consensus/articles/2023/11/compounded-bioidentical-menopausal-hormone-therapy

Compounded Bioidentical Menopausal Hormone Therapy There is a lack of high-quality data on the safety and efficacy of custom-compounded bioidentical hormone therapy for the management of menopausal symptoms.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11896113/

Comparative estrogen exposure from compounded ... This study suggests that women using compounded transdermal estradiol creams may be receiving less estrogen exposure when compared to women using FDA-approved ...

4. fda.gov fda.gov/science-research/advancing-regulatory-science/evaluating-quality-performance-extemporaneously-compounded-estrogen-hormone-products

Performance of Extemporaneously Compounded Estrogen ... This study will enable the FDA to assess the absorption of active ingredients from topically applied compounded estradiol products.

5. journals.lww.com journals.lww.com/menopausejournal/fulltext/2022/04000/safety_and_efficacy_of_compounded_bioidentical.13.aspx

Safety and efficacy of compounded bioidentical hormone... cBHT in the form of compounded vaginal androgen was found to significantly improve vaginal atrophy symptoms (SMD -0.66 [95% CI, -1.28 to -0.04]; I2 = 86.70%).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6808563/

The dangers of compounded bioidentical hormone ... Compounded bioidentical hormone replacement therapy does not carry the safety warnings for estrogen products that are in all prescribed HRT preparations.

7. mayoclinic.org mayoclinic.org/drugs-supplements/estradiol-topical-application-route/description/drg-20573786

Estradiol (topical application route) - Side effects & dosage Estradiol topical emulsion is used to treat moderate to severe symptoms of menopause (eg, feelings of warmth in the face, neck, and chest)

8. bjgp.org bjgp.org/content/69/688/540

The dangers of compounded bioidentical hormone ... Compounded bioidentical hormone replacement therapy does not carry the safety warnings for estrogen products that are in all prescribed HRT preparations.