Menopausal hot flashes: mechanisms, endocrinology, treatment. Original paper

What was reviewed?

This comprehensive review synthesizes the current understanding of the mechanisms, endocrinology, and treatment options for menopausal hot flashes (HFs), emphasizing their physiological, neuroendocrine, and thermoregulatory underpinnings. The review details the characteristic clinical features of HFs, sudden intense warmth, sweating, and peripheral vasodilation, and investigates their temporal association with small core body temperature (Tc) elevations within a markedly narrowed thermoneutral zone. Freedman discusses the role of estrogen withdrawal, central sympathetic activation (particularly through α2-adrenergic receptors), and the complex neuroendocrine interactions involving norepinephrine (NE), serotonin (5-HT), and other neurotransmitters. The review also evaluates objective measurement techniques for HFs, including skin conductance and ambulatory monitors, and synthesizes findings from imaging studies exploring brain activation patterns during HFs. Treatment modalities, both hormonal and nonhormonal, including behavioral interventions, clonidine, serotonergic agents, isoflavones, and gabapentin, are critically reviewed in terms of efficacy and underlying mechanisms.

Who was reviewed?

The review encompasses findings from diverse populations: primarily peri- and postmenopausal women experiencing natural or surgical menopause, with some comparisons to asymptomatic women and men undergoing androgen deprivation for prostate cancer. Epidemiological data highlight racial and ethnic differences in HF prevalence (Caucasian women highest, Japanese and Chinese women lowest). Key physiological, endocrinological, and neuroimaging studies included both symptomatic and asymptomatic women, as well as breast cancer survivors who often experience treatment-induced HFs. Clinical trials of various treatments involved postmenopausal women with frequent HFs, including those with sleep complaints, and studies of objective HF measurement extended to men receiving GnRH agonists. The review thus offers a broad perspective, integrating findings from clinical, laboratory, and ambulatory settings across multiple demographic groups.

Most important findings

Menopausal hot flashes are characterized by a rapid, exaggerated heat dissipation response, sweating, vasodilation, and a feeling of internal heat, triggered by minimal Tc elevations within a greatly reduced thermoneutral zone. This narrowing is not solely attributable to estrogen depletion: while estrogen therapy effectively eliminates HFs, estrogen levels do not robustly correlate with HF presence or frequency, and additional factors must contribute. Elevated central sympathetic activity, mediated by α2-adrenergic receptors, appears critical in narrowing the thermoneutral zone; pharmacologic manipulation directly affects HF incidence. Objective monitoring via skin conductance and novel ambulatory devices provides reliable HF measurement, overcoming biases of self-reporting. Imaging studies demonstrate that the insular cortex, anterior cingulate, and brainstem are sequentially activated during HFs, linking physiological events to subjective experience. Treatment reviews show hormone therapy as the most effective, but nonhormonal options like paced respiration and clonidine are substantiated; SSRIs/SNRIs have mixed efficacy, and the role of serotonin is increasingly questioned. Botanical therapies show inconsistent benefit. Gabapentin exhibits moderate efficacy with known side effects. The review does not identify direct microbial associations or microbiome signatures related to HFs, and the role of the microbiome remains unaddressed in this context.

Key implications

For clinicians, this review underscores the multifactorial etiology of menopausal hot flashes, with central neuroregulatory dysfunction, rather than estrogen deficiency alone, being paramount. Treatments targeting central sympathetic tone (e.g., clonidine, behavioral relaxation) are rational, especially for women unwilling or unable to use hormone therapy. Objective monitoring methods, including skin conductance and ambulatory devices, may improve both diagnosis and evaluation of treatment response. The findings support individualized treatment, emphasize the need for thorough sleep disorder assessment in symptomatic women, and highlight areas for future research, particularly regarding central neuroregulatory pathways and novel therapeutic targets.