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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the connection between hot flashes and the risk of heart problems in women. Researchers focus on how blood vessel and nerve responses might link these issues. Participants will receive treatments like norepinephrine, which narrows blood vessels and raises blood pressure, and will be exposed to certain stressors to observe effects on blood vessels and nerves. Women who do not smoke, are not obese, have at least one ovary, and are not on certain heart-related medications may qualify. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could lead to new insights into women's health.

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.

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

Research has shown that norepinephrine, one of the treatments in this study, has been used in medical settings for various conditions. Although not primarily used for treating hot flashes, it is generally safe under a doctor's care. Like any medication, it can have side effects. Norepinephrine may increase heart rate or blood pressure, but healthcare providers typically monitor and manage these effects.

The study also includes conditions that might increase the activity of the sympathetic nervous system, which controls the "fight or flight" response. Specific safety data for these conditions in this study is limited. Because this research is exploratory, closely monitoring safety will be crucial to ensure participants' well-being.

This trial is labeled as "Not Applicable" for phase, indicating a focus on understanding the process rather than testing a new drug's safety or effectiveness. As a result, the safety of the treatments in this context might not be as well-established as in later-stage trials or approved uses. Participants should discuss potential risks and safety measures with the study team in detail. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how norepinephrine and sympathoexcitatory stressors impact neurovascular responses during hot flashes. Unlike standard treatments for hot flashes, which often include hormone replacement therapy or medications like antidepressants, this study looks at the body's microvascular and autonomic functions. By understanding these unique physiological responses, scientists hope to uncover new insights that could lead to more targeted and effective interventions for managing hot flashes.

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

Research has shown that norepinephrine, a brain chemical, might help reduce the frequency of hot flashes. Some studies have found a significant decrease in both the number and intensity of hot flashes with treatments similar to norepinephrine. For instance, one study reported a 47% decrease in hot flash frequency compared to a placebo. However, not all treatments completely manage the symptoms. While norepinephrine's role in hot flashes is not fully understood, its effect on the body's stress response is under investigation. Participants in this trial will contribute to further exploring these effects. ^{6 7 8 9 10}

Who Is on the Research Team?

Sarah Baker, PhD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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, 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2765998/

Norepinephrine activity, as measured by MHPG, is associated ... These data indicate that MHPG may not be an effective biomarker of the hot flush experience during menopause. Freedman and Woodward measured MHPG at 60-min ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9938702/

Vasomotor Symptoms During Menopause: A Practical Guide ... This review aims to summarize treatment options for bothersome vasomotor symptoms to guide clinicians caring for midlife women.

3. aafp.org aafp.org/pubs/afp/issues/2022/0400/p430.html

SSRIs vs. SNRIs for Vasomotor Symptoms of Menopause One study (n = 205) found a significant reduction in hot flash frequency (47% vs. 33%; P < .001) and severity (24% vs. 14%; P < .001) when compared with placebo ...

4. ajog.org ajog.org/article/S0002-9378%2806%2902476-8/fulltext

Vasomotor symptoms in menopause: physiologic condition ... At 900 mg/d, the frequency of hot flashes dropped by 41% and 44% at weeks 4 and 8, respectively, significantly greater than placebo (18%, P < .0001; 15%, P = .

5. sciencedirect.com sciencedirect.com/science/article/pii/S0378512222001360

Evaluation of the impact, treatment patterns, and patient ... Of women currently prescribed treatment for VMS, only 31.1 % had full control of hot flashes and 33.7 % had full control of night sweats, whereas 16.0 % and ...

6. cdn.pfizer.com cdn.pfizer.com/pfizercom/products/material_safety_data/LEVOPHED_norepinephrine_inj_hospira_17-aug-2016.pdf

SAFETY DATA SHEET Note: This document has been prepared in accordance with standards for workplace safety, which requires the inclusion of all known hazards ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK539827/

Hot Flashes - StatPearls - NCBI Bookshelf [6] The safety of HT is controversial. The Women's Health Initiative (WHI) is the largest study of its kind that evaluated hormone therapy risks in menopausal ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21319867/

Non-hormonal treatment strategies for vasomotor symptoms In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years.

9. mypcnow.org mypcnow.org/fast-fact/hot-flashes-in-palliative-care-part-2/

Hot Flashes in Palliative Care - Part 2 Hot flashes ('flushes') are a common and disabling symptom, particularly when caused by cancer treatment.

10. hemonc.medicine.ufl.edu hemonc.medicine.ufl.edu/files/2013/07/HotFlashes.pdf

hot flashes/menopausal symptoms Common in post and peri-menopausal women. Prevalence increased in women with breast cancer. Often occur earlier in women with breast cancer.