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

26 Participants Needed

Trial Summary

What is the purpose of this trial?

Twenty-six otherwise healthy adults between 18-40 years of age composed of 13 males and 13 females will be enrolled in this study to determine how sex and sex hormones influence cerebral blood flow (CBF) control in healthy young adults without confounds of age or disease. Participants can expect to be on study for approximately 16 days.

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 data supports the effectiveness of the drug Anastrozole in improving cognitive functions?

Research indicates that Anastrozole, an aromatase inhibitor, can improve spatial learning and memory in rats by counteracting the negative effects of testosterone on these cognitive functions. ^{1 2 3 4 5}

Is testosterone generally safe for use in humans?

Research indicates that testosterone can cause both beneficial and harmful effects, such as improving memory in some cases but worsening neurological impairment in others. Safety may depend on the specific condition being treated and the presence of other medications. ^{2 3 4 6 7}

How does this drug affect brain blood flow differently from other treatments?

This drug, involving hormones like estradiol and alphaMSH, uniquely affects brain blood flow by either increasing or decreasing it in specific brain regions. Estradiol increases blood flow, especially in areas like the frontal cortex and hippocampus, while alphaMSH decreases it, except in the occipital cortex. These effects are distinct from other treatments that may not target these specific brain regions or have such rapid and region-specific impacts. ^{2 8 9 10 11}

Research Team

William G Schrage, PhD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Pharmacokinetics of testosterone and estradiol gel preparations in healthy young men. [2013]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Mechanisms of vasorelaxation to testosterone in the rat aorta. [2019]

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

Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. [2019]

4. Netherlands 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. [2018]

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

Cognitive effects of short-term manipulation of serum sex steroids in healthy young men. [2014]

6. Egypt pubmed.ncbi.nlm.nih.gov

Flutamide Enhances Neuroprotective Effects of Testosterone during Experimental Cerebral Ischemia in Male Rats. [2021]

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

Effects of the nonsteroidal aromatase inhibitor, Fadrozole, on sexual behavior in male rats. [2019]

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

Hormones and regional brain blood flow. [2019]

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

Influence of sex steroid hormones on cerebrovascular function. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Local oestrogenic/androgenic balance in the cerebral vasculature. [2022]

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

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