Neurovascular Responses to Hot Flashes

Overseen By Nancy J Meyer

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Mayo Clinic

Must not be taking: Cardiovascular medications

Disqualifiers: Smoking, Obesity, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 2

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Women who experience hot flashes are at greater risk for hypertension and other cardiovascular disease. Neurovascular control mechanisms are likely to play an important role in this relationship. As such, these studies are designed to provide a major step forward in understanding the link between hot flashes and neurovascular dysfunction and, by extension, cardiovascular disease in women.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that influence cardiovascular function to participate in this trial.

What data supports the effectiveness of the drugs used in the clinical trial for treating hot flashes?

The research indicates that hot flashes are associated with changes in catecholamine levels, such as norepinephrine, which is one of the drugs being studied. This suggests that targeting these changes with norepinephrine-related treatments could potentially help manage hot flashes. ^{1 2 3 4 5}

How does the drug norepinephrine differ from other treatments for hot flashes?

Norepinephrine is unique because it targets the thermoregulatory processes in the brain, specifically affecting the hypothalamic preoptic area, which is involved in heat dissipation. This approach is different from other treatments like estrogen, which works through unknown mechanisms, or clonidine, which reduces central sympathetic activation to widen the thermoneutral zone. ^{1 6 7 8 9}

Research Team

Sarah Baker, PhD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for non-obese women who are not on cardiovascular medications, have at least one ovary, do not smoke, and are free from cardiovascular diseases. It aims to understand the connection between hot flashes during menopause and risks of hypertension.

Inclusion Criteria

I am not on any medications that affect heart function.

I do not have any heart diseases.

Non-obese

Exclusion Criteria

N/A

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Study Visits

Participants undergo assessments of hot flash frequency, microvascular function, and autonomic function

1-2 visits

1-2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after study visits

4 weeks

Treatment Details

Interventions

• Acetylcholine
• Norepinephrine
• Sodium Nitroprusside
• Sympathoexcitatory stressors
• Terbutaline

Trial Overview The study tests how substances like Norepinephrine affect blood vessels and heart function in women with hot flashes. It looks at body responses to stressors and drugs that influence blood pressure and flow during menopausal changes.

Participant Groups

Group I: Experimental: Healthy Women Volunteers Experimental Treatment 5 Interventions

Hot Flash frequency will be assessed in the study subjects during a screening period. Participants can then chose to participate 1 or 2 study visits- Protocol 1: Microvascular function and/or Protocol 2: Autonomic function

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

Approved in United States as Levophed for:

• Severe, acute hypotension
• Cardiac arrest

Approved in Canada as Norepinephrine Bitartrate for:

• Severe, acute hypotension
• Cardiac arrest

Approved in European Union as Noradrenaline for:

• Severe, acute hypotension
• Cardiac arrest

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 11 post-menopausal women, hot flashes were linked to significant increases in plasma epinephrine (about 150%) and decreases in norepinephrine (about 40%), indicating a strong hormonal response during these episodes.

The research established a clear sequence of physiological changes during hot flashes, including increased heart rate and blood flow, a rise in finger temperature by an average of 3.9 degrees Celsius, and a drop in esophageal temperature, supporting the idea that hot flashes result from a shift in the body's thermoregulatory set point.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes. Kronenberg, F., Cote, LJ., Linkie, DM., et al.[2019]

In a study of 150 recently postmenopausal women, cardiovascular risk markers related to heart rate variability did not show a clear link to the frequency or severity of hot flashes.

However, during hot flash episodes, there was a significant increase in the very-low-frequency component of heart rate variability and a slight rise in heart rate, suggesting that hot flashes may alter autonomic control of heart rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women. Hoikkala, H., Haapalahti, P., Viitasalo, M., et al.[2010]

In a study of 150 recently postmenopausal women, those experiencing hot flushes showed a lower heart rate response during the Valsalva maneuver, indicating a potential shift towards increased sympathetic nervous system activity.

The presence of hot flushes did not significantly affect heart rate variability or blood pressure responses, but there was a trend suggesting that women without hot flushes had higher blood pressure after physical stress, which may indicate a negative impact on cardiovascular health for those with hot flushes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes. Hautamäki, H., Piirilä, P., Haapalahti, P., et al.[2013]

Hot flashes during menopause are linked to a hypothalamic response triggered by declining estrogen levels, affecting up to 75% of women in the US.

Both subjective reports and objective measurements (like sternal skin conductance) can effectively assess hot flashes, with laboratory methods showing high concordance, while ambulatory monitoring provides less consistent results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subjective and objective measures of hot flashes. Sievert, LL.[2013]

In a study of 30 postmenopausal women, moclobemide significantly reduced the severity of hot flashes, with a 69.8% reduction in the lower dose group (150 mg) compared to only 24.4% in the placebo group, indicating its efficacy beyond placebo effects.

Moclobemide presents a promising nonhormonal treatment option for managing hot flashes in women who prefer not to use estrogen or have contraindications to it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moclobemide in the treatment of hot flashes in postmenopausal women. Tarim, E., Bagis, T., Kilicdag, E., et al.[2019]

In a study involving 19 postmenopausal women, clonidine was found to significantly increase the sweating threshold in women experiencing hot flashes, suggesting it may help alleviate this symptom.

Conversely, clonidine lowered the sweating threshold in women without hot flashes, indicating that its effects may vary based on the presence of menopausal symptoms and highlighting the role of norepinephrine in regulating sweating.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Freedman, RR., Dinsay, R.[2019]

Hot flashes, common during menopause, are linked to a reduced thermoneutral zone in symptomatic women, indicating that even small temperature increases can trigger these symptoms.

Clonidine has been shown to alleviate hot flashes by reducing central sympathetic activation and widening the thermoneutral zone, while estrogen effectively eliminates hot flashes, although its exact mechanism remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiology of hot flashes. Freedman, RR.[2013]

In ovariectomized rats, low estrogen levels led to increased expression of TRPV1 in the hypothalamic preoptic area (POA), which is associated with the development of hot flashes, while norepinephrine (NE) levels and α2-adrenergic receptor (α2-ADR) expression decreased.

Estrogen treatment reversed the changes in TRPV1 and α2-ADR expression, suggesting that the regulation of TRPV1 by NE-activated α2-ADR is a key mechanism in the onset of hot flashes during menopause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in TRPV1 expression in the POA of ovariectomized rats regulated by NE-dependent α2-ADR may be involved in hot flashes. Sun, Y., Wang, W., Zhou, C., et al.[2021]

In ovariectomized (OVX) rats, the lack of estradiol (E2) led to increased tail skin temperature (TST), which was prevented by E2 treatment, indicating that E2 plays a crucial role in regulating body temperature and preventing hot flushes.

The study found that norepinephrine influences kisspeptin neurons in the hypothalamus, suggesting that the imbalance of this neuroendocrine pathway may contribute to the vasomotor symptoms experienced during postmenopausal hot flushes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Norepinephrine modulation of heat dissipation in female rats lacking estrogen. Fonseca, CS., Aquino, NSS., Goncalves, GKN., et al.[2022]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes. [2019]

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

Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women. [2010]

3. Ireland pubmed.ncbi.nlm.nih.gov

Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes. [2013]

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

Subjective and objective measures of hot flashes. [2013]

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

Moclobemide in the treatment of hot flashes in postmenopausal women. [2019]

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

Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. [2019]

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

Physiology of hot flashes. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Changes in TRPV1 expression in the POA of ovariectomized rats regulated by NE-dependent α2-ADR may be involved in hot flashes. [2021]

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

Norepinephrine modulation of heat dissipation in female rats lacking estrogen. [2022]