Hormone Effects on Brain Blood Flow

Overseen By Shawn Bolin, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Wisconsin, Madison

Must not be taking: Cardiovascular medications, Hormonal birth control

Disqualifiers: Hypertension, Diabetes, Heart disease, others

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

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

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how sex and sex hormones affect blood flow in the brain among healthy young adults. Participants will receive various treatments, including testosterone gel (a form of testosterone), estradiol, or a placebo, to assess their impact on brain blood flow. The study includes several groups to compare the effects of hormone suppression and hormone add-back. It suits healthy individuals who completed Phase 1 of Study 2020-0336, are between 18-40 years old, and do not have conditions like high blood pressure or diabetes. As a Phase 4 trial, the treatments are already FDA-approved and proven effective, aiming to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial requires that women stop taking hormonal birth control at least one month before the study if it's used for contraception only. Other medications, especially cardiovascular ones, may also need to be stopped, as their use is listed as an exclusion criterion.

What is the safety track record for these treatments?

Research has shown that indomethacin, one of the treatments in this trial, is well-studied. In healthy adults, it can cause short-term changes in blood flow to the brain, but these effects typically last less than a week, indicating the drug is generally safe for short-term use. Some individuals might experience common side effects like an upset stomach or dizziness.

Estradiol and testosterone gel are also part of this study. Both have been safely used for other health conditions. Estradiol, a type of estrogen, plays a crucial role in many body functions. Testosterone gel helps increase testosterone levels. These treatments are usually well-tolerated, though some people might experience mild side effects like skin reactions or mood changes.

Anastrozole and Orilissa adjust hormone levels. Anastrozole is often used in breast cancer treatment, while Orilissa helps with endometriosis pain. They are generally safe, but some users may experience side effects like hot flashes or tiredness.

As this is a phase 4 trial, these treatments have been tested in large groups before, providing extensive information about their safety. While side effects can occur, these treatments are generally considered safe for short-term use in healthy adults. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they investigate how different hormones and hormone blockers like Anastrozole, Estradiol, Indomethacin, Orilissa, and Testosterone gel affect brain blood flow. Unlike traditional treatments that primarily focus on hormone replacement or suppression in isolation, this study looks at the combined impact of adding or suppressing multiple hormones simultaneously. This approach could offer new insights into how hormonal changes influence brain function and potentially lead to breakthroughs in managing conditions related to hormone fluctuations. By exploring these unique interactions, researchers hope to uncover new ways to optimize hormone therapies for better brain health outcomes.

What evidence suggests that this trial's treatments could be effective for influencing cerebral blood flow?

Research has shown that treatments like Anastrozole, Estradiol, Indomethacin, Orilissa, and Testosterone gel can affect blood flow in the brain. In this trial, participants will receive different treatments in separate arms. For instance, Indomethacin, administered to some participants, quickly reduces blood flow in the brain after intake. This reduction often links to more efficient oxygen use by the brain. Estradiol and Testosterone, included in other treatment arms, may alter blood flow patterns due to their role in hormone regulation. Anastrozole and Orilissa, also studied in this trial, affect hormone levels and are being explored for their potential to change brain blood flow. These treatments aim to understand how hormones impact brain activity and blood flow in healthy adults. ^{6 7 8 9 10}

Who Is on the Research Team?

William G Schrage, PhD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-40 who want to help understand how sex and hormones affect brain blood flow. The study will include an equal number of males and females, totaling 26 participants.

Inclusion Criteria

Completed Phase 1: Study 2020-0336

Exclusion Criteria

Fasting blood glucose ≥100 mg/dl

NSAID sensitivity

I have or had liver disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 days

Hormone Suppression

Participants undergo hormone suppression using Orilissa and Anastrozole, followed by MRI visits to assess CBF under hypoxia and hypercapnia conditions.

7 days

2 MRI visits

Hormone Add-Back

Participants receive sex hormone add-back (testosterone for males, estradiol for females) and undergo MRI visits to assess CBF under hypoxia and hypercapnia conditions.

12-16 days

2 MRI visits

Follow-up

Participants are monitored for safety and effectiveness after the completion of MRI visits.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Anastrozole
• Estradiol
• Indomethacin
• Orilissa
• Testosterone gel

Trial Overview The study tests the effects of testosterone gel, placebo, Anastrozole (blocks estrogen production), Orilissa (alters hormone levels), Indomethacin (a pain reliever), and Estradiol (a form of estrogen) on brain blood flow in response to stress.

How Is the Trial Designed?

Group I: Placebo First: Hormone Suppression Experimental Treatment 4 Interventions

Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.

Group II: Placebo First: Hormone Add-Back Experimental Treatment 6 Interventions

Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.

Group III: Indo First: Hormone Suppression Experimental Treatment 3 Interventions

Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.

Group IV: Indo First: Hormone Add-Back Experimental Treatment 6 Interventions

Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.

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+

Published Research Related to This Trial

Sex steroids, such as estrogen and androgens, significantly influence cerebral blood vessels by altering vascular tone, endothelial function, oxidative stress, and inflammation, indicating their role beyond reproductive tissues.

Cerebral blood vessels not only respond to circulating sex hormones but also produce their own sex steroids locally, which can affect vascular function and may contribute to differences in cerebrovascular health between genders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local oestrogenic/androgenic balance in the cerebral vasculature. Krause, DN., Duckles, SP., Gonzales, RJ.[2022]

AlphaMSH administration in adult rats led to a transient reduction in blood flow to most brain regions, which may explain its effects on visual learning and behavior, while neonatal pretreatment with alphaMSH resulted in lasting behavioral changes without corresponding blood flow differences.

In contrast, estradiol increased blood flow to several brain areas, particularly in females, suggesting a strong physiological basis for its behavioral effects, potentially more significant than those caused by other behavior-modifying drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormones and regional brain blood flow. Goldman, H., Skelley, EB., Sandman, CA., et al.[2019]

Sex steroids, particularly 17β-estradiol, significantly influence cerebrovascular function and brain health, affecting both normal physiology and responses to injuries like strokes, but the exact mechanisms are complex and depend on various factors such as dosage and underlying health conditions.

Androgens like testosterone and dihydrotestosterone have less clear effects on cerebrovascular function, with some studies suggesting they can have both beneficial and harmful impacts, indicating a need for further research to clarify their roles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Androgens and the cerebrovasculature: modulation of vascular function during normal and pathophysiological conditions. Gonzales, RJ.[2021]

Testosterone induces acute vasorelaxation in the rat aorta, and this effect is enhanced by cyclooxygenase inhibitors like indomethacin, suggesting that endothelium-derived prostanoids play a role in this process.

The vasorelaxant effects of testosterone are mediated through the activation of calcium-activated potassium (K(Ca)) channels and involve inhibition of calcium influx at higher concentrations, indicating a complex mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of vasorelaxation to testosterone in the rat aorta. Tep-areenan, P., Kendall, DA., Randall, MD.[2019]

This study provides the first pharmacokinetic data on testosterone and estradiol gel formulations in healthy young men, showing that testosterone gel reaches peak serum levels three hours after application without suppressing LH, cortisol, or SHBG levels.

Estradiol gel achieves peak serum levels two hours post-application, also without suppressing cortisol, SHBG, or LH, indicating that both gels can be safely administered without negatively affecting these hormonal levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of testosterone and estradiol gel preparations in healthy young men. Eisenegger, C., von Eckardstein, A., Fehr, E., et al.[2013]

Testosterone (TE) and estradiol (EV) negatively impacted spatial learning and memory in rats, as shown by increased escape latency and distance traveled in the Morris water maze, indicating potential impairments in cognitive function.

The aromatase inhibitor anastrozole improved spatial learning and memory performance, suggesting it can counteract the negative effects of testosterone on cognitive abilities, although it did not buffer the effects of estradiol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats. Moradpour, F., Naghdi, N., Fathollahi, Y.[2018]

Estrogens have protective effects on the cerebral vasculature by enhancing blood flow and reducing inflammation, while testosterone increases vascular tone and inflammation, indicating a complex interplay between these hormones in brain health.

Most research on sex steroids and cerebral blood vessels has focused on young, healthy animals, suggesting that the effects of these hormones may differ significantly in older individuals or those with conditions like diabetes, which is crucial for understanding gender differences in stroke and other cerebrovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of sex steroid hormones on cerebrovascular function. Krause, DN., Duckles, SP., Pelligrino, DA.[2022]

In a study of 32 healthy young men, reducing testosterone levels with levonorgestrel (LNG) led to a significant decrease in verbal memory performance, indicating that lower testosterone can negatively impact cognitive function.

Conversely, when testosterone was administered alongside LNG, it helped maintain verbal memory and improved divided attention, suggesting that testosterone plays a protective role in cognitive functioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive effects of short-term manipulation of serum sex steroids in healthy young men. Cherrier, MM., Anawalt, BD., Herbst, KL., et al.[2014]

Fadrozole, a nonsteroidal aromatase inhibitor, effectively blocked the conversion of testosterone to estradiol in the brains of castrated male rats, demonstrating a reduction of over 96% in brain aromatase activity at a low dose of 0.25 mg/kg.

Treatment with Fadrozole significantly suppressed male sexual activity, with a 77% reduction in ejaculations and a 48% reduction in intromissions compared to controls, indicating that aromatization of testosterone is crucial for sexual behavior in male rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the nonsteroidal aromatase inhibitor, Fadrozole, on sexual behavior in male rats. Bonsall, RW., Clancy, AN., Michael, RP.[2019]

In a study involving 50 rats subjected to a 60-minute middle cerebral artery occlusion, castration reduced brain damage and improved neurological function, suggesting that testosterone may have harmful effects during cerebral ischemia.

The use of flutamide, an androgen receptor blocker, was found to enhance neuroprotection and improve outcomes better than castration alone, while letrozole, which blocks testosterone aromatization, increased brain damage and seizures, indicating a complex relationship between testosterone and brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flutamide Enhances Neuroprotective Effects of Testosterone during Experimental Cerebral Ischemia in Male Rats. Fanaei, H., Sadeghipour, HR., Karimian, SM., et al.[2021]

In hypogonadal men treated with testosterone gel, significant improvements in verbal memory were observed after 90 days, alongside increased levels of testosterone and estradiol, indicating that testosterone replacement can enhance cognitive function.

For older hypogonadal men treated with dihydrotestosterone gel, spatial memory improved significantly after 90 days, suggesting that while testosterone levels decreased, dihydrotestosterone may specifically benefit spatial cognitive abilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. Cherrier, MM., Craft, S., Matsumoto, AH.[2019]

Citations

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Indomethacin: a review of its cerebral blood flow effects ... Case series involving severe TBI patients suggest that IND i.v. boluses of 30-50 mg reduce ICP by 37%-52%, reduce CBF by 22%-26%, with a modest 14% increase in ...

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Indomethacin markedly blunts cerebral perfusion and ... Indomethacin reduced MCAv mean and impaired cognition slightly; however, no clear association was evident in younger or older adults.

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Differential effects of ibuprofen and indomethacin on ... Indomethacin significantly reduces cerebral blood flow soon after administration, resulting in a parallel increase in oxygen extraction and arterial lactate.

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A Review of its Role in the Management of Traumatic Brain ... Indomethacin should only be considered as an experimental therapy for refractory intracranial hypertension in TBI patients.

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Indomethacin: Uses, Interactions, Mechanism of Action In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood ...

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Indomethacin Capsules, USP 25 mg Rx only WARNING In one study after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The clinical ...

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Indomethacin: uses, dosing, warnings, adverse events, ... Indomethacin is used orally or rectally for anti-inflammatory and analgesic effects in the symptomatic treatment of moderate to severe rheumatoid arthritis.

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Indomethacin - StatPearls - NCBI Bookshelf - NIH Indomethacin's high lipid solubility facilitates easy crossing of the blood-brain barrier. Additionally, it achieves high concentrations in ...

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NCT04265053 | Human Cerebral Blood Flow Regulation Indomethacin is used to test COX as a potential mechanism explaining sex differences in CBF control. Indomethacin usage is IND exempt. Drug : Ganirelix Acetate.