Medications for Cerebral Blood Flow Regulation

(Gas Challenge Trial)

Overseen By Shawn E Bolin, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Wisconsin, Madison

Must not be taking: Cardiovascular, Hormonal birth control

Disqualifiers: Obesity, Diabetes, Hypertension, Smoking, others

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

Compensation: Varies

Number of Visits: Unknown

111 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are taking cardiovascular medications or hormonal birth control, you will need to stop, as these are not allowed in the trial.

What data supports the effectiveness of the drug Estradiol Transdermal for cerebral blood flow regulation?

Research on transdermal estradiol, like the Menorest patch, shows it maintains consistent estradiol levels in the blood, which could suggest stable hormone delivery that might help regulate cerebral blood flow. ^{1 2 3 4 5}

Is transdermal estradiol safe for humans?

Transdermal estradiol has been shown to be well tolerated in clinical studies, with no adverse biochemical changes and limited minor side effects like fluid retention. It avoids the cardiovascular toxicity associated with oral estrogen and has a low incidence of endometrial hyperplasia and breast tenderness. ^{1 2 4 6 7}

How does the drug for cerebral blood flow regulation differ from other treatments?

This drug is unique because it uses 17beta-estradiol, a form of estrogen, administered intranasally to potentially increase cerebral blood flow, which is different from other treatments that may not use this hormone or administration route. ^{8 9 10 11 12}

What is the purpose of this trial?

This study tests basic differences in how men and women control brain (cerebral) blood flow (CBF), at rest and under stress. The stress is low oxygen or high carbon dioxide. The investigators hypothesize that sex differences per se, plus sex hormone differences, drive different signals in blood vessels that change the way CBF is regulated. The investigators will test these mechanisms with medicine infusions during stress, and measure CBF using state-of-the-art MRI approaches. Research confounding variables like aging and disease will be mitigated by comparing younger adults (18-40 years old).

Research Team

William Schrage, PhD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

Healthy adults aged 18-40 with normal blood pressure, body mass index (BMI) between 19-25, regular menstrual cycles for women, and good cholesterol levels. Excluded are those with a history of stroke, diabetes, kidney or blood diseases, obesity, sleep apnea; smokers; users of hormonal birth control or cardiovascular meds; pregnant women; and anyone unable to undergo MRI.

Inclusion Criteria

I have a regular menstrual cycle without any interventions.

Your blood pressure is lower than 125/80 mm Hg (millimeters of mercury).

Your blood sugar level should be normal (less than 100 mg/dL).

Exclusion Criteria

I have had a stroke in the past.

You smoke cigarettes regularly.

Your current blood pressure is higher than 130/85 mmHg.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1

Participants undergo MRI and pharmacologic testing to study CBF control mechanisms under hypoxia and hypercapnia conditions.

Up to 14 days

Multiple visits (in-person)

Phase 2

Participants repeat Phase 1 procedures with sex hormone suppression and single hormone replacement to study the impact on CBF control.

Up to 14 days

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Estradiol Topical
• Ganirelix Acetate
• Ketorolac Tromethamine
• L-NMMA
• Testosterone Transdermal Product

Trial Overview The study is examining how men and women regulate brain blood flow at rest and under stress from low oxygen or high carbon dioxide. It involves infusions of Ganirelix Acetate, L-NMMA, Ketorolac Tromethamine along with Estradiol Topical for women and Testosterone Transdermal Product for men while using advanced MRI to measure changes in cerebral blood flow.

Participant Groups

Group I: Male NOS Experimental Treatment 4 Interventions

Males visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group II: Male COX Experimental Treatment 4 Interventions

Males visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group III: Female NOS Experimental Treatment 4 Interventions

Females visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group IV: Female COX Experimental Treatment 4 Interventions

Females visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Menorest is a new transdermal patch that delivers 17 beta-estradiol in a microfine suspension, making it thinner and more cosmetically appealing than older patches.

It effectively maintains plasma estradiol levels at or above the target of 40 pg/ml for the entire 80-hour dosing period, demonstrating consistent and reliable hormone delivery across various doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New trends in transdermal technologies: development of the skin patch, Menorest. Marty, JP.[2016]

In a long-term study involving 1694 men with prostate cancer, transdermal oestradiol (tE2) patches showed no significant difference in cardiovascular morbidity or mortality compared to luteinising hormone releasing hormone agonists (LHRHa), suggesting tE2 is a safe alternative for androgen suppression.

The study also found that tE2 patches resulted in fewer adverse effects like gynaecomastia and hot flushes compared to LHRHa, indicating a potentially better tolerability profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Langley, RE., Gilbert, DC., Duong, T., et al.[2023]

In a study involving 24 healthy women, the contraceptive patch delivered steady-state levels of norelgestromin (NGMN) and ethinyl estradiol (EE) consistently over three cycles, indicating effective and reliable hormone delivery.

The treatment was well tolerated with excellent patch adhesion, and there was minimal accumulation of the hormones over time, suggesting a safe profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Abrams, LS., Skee, DM., Natarajan, J., et al.[2019]

Transdermal testosterone patches are being developed for women, particularly for treating sexual dysfunction in menopausal women, and are currently in phase III clinical trials.

Preliminary phase II studies indicate that the testosterone matrix patch is effective and safe for women with sexual dysfunction, showing promise as a new method for androgen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal testosterone for women: a new physiological approach for androgen therapy. Mazer, NA., Shifren, JL.[2013]

In a study involving a once-weekly transdermal estradiol patch applied to either the buttocks or abdomen, the buttock application resulted in significantly higher estradiol levels, with a 125.1% peak concentration compared to the abdomen.

The buttocks provided better bioavailability of estradiol, which may benefit women experiencing menopausal symptoms, as it maintained higher hormone levels throughout the week.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara). Taggart, W., Dandekar, K., Ellman, H., et al.[2019]

In a study of 93 transgender women and gender nonbinary adults, sublingual 17β-estradiol tablets resulted in significantly higher estrone concentrations compared to transdermal or injectable forms, indicating differences in hormone absorption and metabolism based on the delivery method.

Estradiol levels above 200 pg/mL were linked to higher estrone levels in those using sublingual tablets, but this association was not observed with transdermal or injectable forms, suggesting that the method of administration may influence hormone interactions and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. Cirrincione, LR., Winston McPherson, G., Rongitsch, J., et al.[2021]

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]

In a study involving 18 healthy postmenopausal women, intranasal administration of 17beta-estradiol significantly increased cerebral blood flow (CBF) volume compared to a placebo.

The increase in CBF volume was attributed to the vasodilatatory effects of 17beta-estradiol on the internal carotid and vertebral arteries, although no changes were observed in flow velocities or pulsatility indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Aerodiol administration on cerebral blood flow volume in postmenopausal women. Acar, M., Cevrioglu, AS., Haktanir, A., et al.[2016]

Raloxifene, a selective estrogen receptor modulator (SERM), effectively relaxes rat cerebral arteries by inhibiting calcium influx through L-type calcium channels, indicating a potential therapeutic role in cerebrovascular health.

The relaxation effect of raloxifene occurs independently of the endothelium, suggesting that it may provide cardiovascular benefits without the carcinogenic risks associated with traditional estrogen therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels. Tsang, SY., Yao, X., Essin, K., et al.[2016]

Intracarotid infusion of estrogen did not increase cerebral blood flow (CBF) in rabbits, indicating that systemic estrogen may not enhance blood flow under steady-state conditions.

Topical application of estradiol on pial arterioles did cause vasodilation, but only at specific concentrations, and this effect was blocked by the antiestrogen tamoxifen, highlighting the role of estrogen receptors in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits. Littleton-Kearney, MT., Agnew, DM., Traystman, RJ., et al.[2020]

In female rats, the combination of vitamin D deficiency and testosterone treatment led to significant changes in the anterior cerebral arteries, including decreased lumen size and increased wall thickness, indicating potential risks for cerebrovascular health.

In male rats, vitamin D deficiency alone caused similar adverse effects on the cerebral arteries, suggesting that both hyperandrogenism and vitamin D deficiency can negatively impact vascular health and increase stroke risk, with gender differences in how these factors interact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries. Pál, É., Hadjadj, L., Fontányi, Z., et al.[2020]

In a study involving 23 postmenopausal women, 17 beta-oestradiol was found to significantly induce vasodilation in femoral arteries, increasing their diameter by an average of 6.4% and blood flow by 30%, indicating its efficacy in improving vascular function.

The study suggests that the vasodilatory effects of 17 beta-oestradiol may play a role in reducing the risk of cardiovascular diseases in postmenopausal women, highlighting its potential therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular responses to 17 beta-oestradiol in postmenopausal women. Riedel, M., Oeltermann, A., Mügge, A., et al.[2019]

References

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

New trends in transdermal technologies: development of the skin patch, Menorest. [2016]

2. England pubmed.ncbi.nlm.nih.gov

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. [2023]

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

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. [2019]

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

Transdermal testosterone for women: a new physiological approach for androgen therapy. [2013]

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

The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara). [2019]

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

Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

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

8. Ireland pubmed.ncbi.nlm.nih.gov

Effect of Aerodiol administration on cerebral blood flow volume in postmenopausal women. [2016]

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

Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels. [2016]

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

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits. [2020]

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

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Vascular responses to 17 beta-oestradiol in postmenopausal women. [2019]