A randomized, double-blinded, placebo-controlled trial of uninterrupted transdermal nitrate therapy in 140 peri- or postmenopausal women who have frequent hot flashes. Women will be randomly assigned to uninterrupted use of transdermal nitrate therapy (participant directed dose-escalation of 0.2 to 0.6 mg/hr) or identical-appearing placebo patches for 12 weeks.

Inclusion Criteria:

• Women aged 40 to 62 years (consistent with the recent MSFlash hot flash network trials, and likely to maximize enrollment of highly symptomatic women)
• Postmenopausal or in the late menopausal transition. For this study, postmenopausal status will be defined by: 1) self-reported history of bilateral oophorectomy, 2) follicle stimulating hormone (FSH) levels > 20 mU/mL for those with a self-reported history of hysterectomy without bilateral oophorectomy, or 3) no self-reported history of hysterectomy or oophorectomy, but absence of menses in the past 12 months. Late menopausal transition will be defined by amenorrhea for at least 60 days in the past 12 months within the specified age group.
• Documentation of an average of 7 or more hot flashes per 24 hours as well as 4 or more moderate-to-severe hot flashes per 24 hours as recorded on a validated 7-day screening symptom diary
• Willing to refrain from initiating other treatments that are known to affect the frequency of severity hot flashes during the trial period
• Report having a current primary health care provider (such as a general practitioner, family medicine, internal medicine, or nurse practitioner providing primary care or specializing in women's health)

Exclusion Criteria:

• Current or recent use of NTG or other nitrate-containing medications (i.e., use within 1 month of screening), or intention to use nitrate-containing medication during the interventional period
• Current or recent use of medications already known to reduce the frequency or severity of hot flashes (e.g., vaginal or transdermal estrogens in the past 4 weeks; oral estrogens or progestins in the past 8 weeks; intrauterine progestin therapy in the past 8 weeks; progestin implants or estrogen alone injectable therapy in the past 3 months; estrogen pellet therapy or progestin injectable therapy in the past 6 months; clonidine, methyldopa, gabapentin, pregabalin and selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) in the past 1 month); or intention to use these medications during the interventional period
• Current or recent use of phosphodiesterase inhibitor medications (within 1 month of screening), or intention to use these medications during the interventional period
• Current or recent use of riociguat, a soluble guanylate cyclase stimulator medication, within 1 month of screening, or intention to use riociguat during the interventional period
• Self-reported history of hypertrophic obstructive cardiomyopathy, aortic valve stenosis, or mitral valve stenosis (since symptoms of these conditions may be aggravated by NTG therapy)
• Self-reported history of coronary disease (since patients with coronary disease may need NTG therapy for chest pain or may be at increased risk of new coronary events in the setting of nitrate tolerance), or evidence of prior myocardial infarction on screening electrocardiogram (ECG)
• Self-reported history of diabetes or 2 or more major risk factors for coronary disease (i.e., smoking, hypertension, or hyperlipidemia with physician-recommended pharmacologic treatment)
• Evidence of tachyarrhythmias such as atrial fibrillation or flutter without adequate rate control (>110 beats/minute) on screening ECG
• Evidence of second or third-degree atrioventricular block on screening ECG
• Hypotension based on measured resting blood pressure <90/60 at baseline; or normal resting blood pressure but evidence of orthostatic hypotension with change from supine to standing position)
• Uncontrolled hypertension based on measured resting blood pressure > 180/110 at baseline
• Self-reported headaches interfering with activities of daily activities more than twice a month, or use of prescription medication to prevent or treat headache in the past month (since these may be worsened by NTG therapy)
• Known allergy to nitroglycerin or other nitrate-based medications.
• Known skin sensitivity to adhesives (which may generalize to the NTG patches)
• Unable to complete or tolerate a brief 3-day run-in period involving the lowest available dose of NTG (0.1 mg/hr)
• Currently pregnant, gave birth within the past 3 months, planning pregnancy during the study period, or unwilling to use regular barrier contraception or abstain from sexual activity to prevent pregnancy if not yet postmenopausal
• Currently breastfeeding, breastfeeding within the past 3 months, or planning to breastfeed during the study period
• Self-report heavy alcohol use (>3 drinks in a given day or >7 drinks per week) and uncomfortable or unwilling to decrease their alcohol intake during the study period.
• Unable or unwilling to provide informed consent, fill out questionnaires, or complete study visits in English
• Report other conditions that, in the judgment of the investigators, render potential participants highly unlikely to follow the protocol, including plans to move, substance abuse, significant psychiatric problems, or severe dementia.

16 weeks