In the United States, 16 million adolescents and adults struggle with heavy menstrual bleeding (HMB). HMB is defined as blood loss that requires changing pads/tampons every 2 h or less, requiring more than one pad/tampon at a time, frequent passing of clots or flooding events, or periods lasting 8 days or more (1). Generally, HMB is determined by personal perception of menstrual blood loss and the related effects on quality of life. Heavy menstrual bleeding adversely affects mood, energy, school/work productivity, social interactions, family life, and sexual health (2–6). HMB contributes to negative workplace productivity; 45.2% reporting absenteeism, 48.4% lacking manager support, and 94.6% lacking specific support or wellness programs for menstrual cycle issues (4, 7). In a recent study, 80.7% (n = 26,438) of the respondents reported presenteeism and decreased productivity of an average 23.2 days per year due to menstrual related symptoms (4). HMB may be caused by a variety of factors such as hormonal imbalance, uterine conditions (e.g., fibroids, endometriosis), underlying bleeding disorders including von Willebrand disease (VWD), or other health conditions. Current treatments depend on the underlying etiology, treatment preferences, and pregnancy intentions. In patients with bleeding disorders including von Willebrand disease, HMB is frequently inadequately treated and concomitant therapies are frequently utilized (3). Poor tolerability or acceptability of current treatments suggests that additional non-invasive and non-pharmaceutical solutions are desired (8).

Pre-clinical studies over the past decade have identified a vagal efferent signal to the spleen, termed the “neural tourniquet,” that promotes platelet-mediated hemostasis. Direct cervical vagus nerve stimulation (VNS) reduced bleeding times and shed blood volumes by 45–75% in animal models of soft tissue injury and coagulation factor VIII deficiency (9, 10). Implantable cervical VNS is an FDA-approved treatment for refractory epilepsy, treatment-resistant depression, and chronic ischemic stroke (11). Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to invasive cervical VNS and has been applied for headache, migraine, heart failure, gastric motility disorders, asthma, tinnitus, and other conditions (12, 13). taVNS non-invasively targets the auricular branch of the vagus nerve (ABVN), which has projections to various brainstem nuclei (e.g., the nucleus tractus solitarius). Through centrally mediated activation, the ABVN can modulate vagal afferent and efferent networks (13–19). Stimulation of the ABVN releases central nervous system endorphins (20), shifts circulating monocytes to an anti-inflammatory phenotype (21), inhibits pro-inflammatory cytokine release (22), and has sustained antinociceptive effects (23, 24). A recent systematic review and meta-analysis concluded that taVNS is safe and feasible across several indications (25). Transcutaneous auricular neurostimulation (tAN) is similar to taVNS but delivers stimulation to both the ABVN and the auriculotemporal nerve (ATN), a branch of the trigeminal nerve. By targeting the vagus and trigeminal nerves through auricular stimulation, tAN provides a comprehensive, non-pharmacological and non-invasive solution for managing a wide range of menstrual symptoms, from heavy bleeding and cramping pain to mood changes, gastrointestinal discomfort, and associated autonomic disruptions (13, 26–28). The vagus nerve, whose name derives from the Latin word for “wanderer,” provides extensive connectivity between the brain and various organs (29). This crucial pathway carries predominantly afferent signals, with approximately 80% of vagal fibers transmitting information from the body to the brain, while 20% carry regulatory signals in the opposite direction (25). The trigeminal nerve system, with its three major branches (ophthalmic, maxillary, and mandibular), serves crucial sensory and motor functions in the face and head. Beyond these traditional roles, research has revealed its significant involvement in autonomic regulation (13). The trigeminal nerve has extensive connections with the autonomic nervous system and shares important integration centers with the vagus nerve, particularly in the brainstem (30). This trigeminal-vagal interaction creates a powerful therapeutic opportunity, as stimulation of these pathways can synergistically modulate autonomic function (31, 32). The convergence of both vagal and trigeminal branches near the ear surface provides an ideal access point for therapeutic intervention through auricular neurostimulation.

A recent healthy human subject study (NCT05977946) (33, 34) provided first-in-human results for the use of tAN to activate the neural tourniquet pathway. tAN increased ADP-mediated α granule release, expression of activated glycoprotein (GP)IIb/IIIa on the platelet surface and increased maximum clot strength as measured via thromboelastography (TEG), with no reported thrombotic complications (33, 34). Given these first-in-human observations, we sought to assess the therapeutic potential of tAN therapy to decrease menstrual blood loss and other menstrual symptoms in a prospective, decentralized pilot study of people with HMB with and without VWD.

Of the 108 potential subjects screened for the VWD + HMB cohort, n = 9 ultimately received the study device; one was lost to follow-up after the treatment cycle without data collection, resulting in n = 8 included in the analysis. Of the 51 potential subjects screened for the HMBu cohort, n = 11 ultimately received the study device; 2 were exited before analysis due to inconsistent data reporting, and one was unable to reliably apply the electrode; n = 8 were included in the analysis (see CONSORT diagram, Figure 3). Demographics of the study participants in each cohort are listed in Table 1.

This pilot study demonstrates feasibility and promising therapeutic efficacy greater than 50% blood loss reduction in HMB among those with and without a bleeding disorder, a clinically meaningful result (43). Use of tAN also demonstrated meaningful reduction in total duration of menstruation. Participants reported significant improvements in the frequency and severity of menstrual symptoms, especially pain, as assessed by the CMSS, as well as improved health-related quality of life scores in the RAND-36 for the VWD + HMB cohort. Notably, participants reported spending 30–50% less extra time in bed due to menstrual symptoms. These promising findings are the first in human therapeutic application of tAN to improve menstrual health.

Current treatments depend on the underlying etiology, treatment preferences, and contraception needs. First line medical treatments include hormonal therapies such as oral, transdermal, or vaginal combined estrogen/progestins, progestin intrauterine devices (IUD), injectables, and subdermal implants (44); and non-hormonal therapies, including anti-fibrinolytic drugs (45); or non-steroidal anti-inflammatory drugs (NSAIDs) (46). Hormonal therapies are highly successful and satisfactory but are sometimes associated with adverse effects that include breakthrough bleeding, nausea, weight gain headaches, edema, and depression (47, 48). Non-hormonal treatments are recommended to reduce menstrual blood loss in patients for whom hormonal treatment is not suitable or preferred (44, 49). For example, antifibrinolytics like tranexamic acid (TXA) are generally well-tolerated, but can cause additional discomfort, headache, back pain, nausea, and diarrhea (50). For people with extreme cases of HMB or underlying bleeding disorders, surgical approaches or blood coagulation factor replacement therapy may be warranted. Surgical approaches include endometrial ablation and hysterectomy. Hysterectomy is a major surgery with associated risks. Additional therapeutic options that do not alter the hypothalamic pituitary axis are needed as alternatives to hormonal medications, or as adjunct therapy for those with inadequate treatment outcomes.

Hormone therapy can often result in complete cessation of menstruation for some users. However, menstruation can occur with some formulations, especially oral contraceptives that include a placebo week. In this study, 62.5% of VWD + HMB cohort participants reported taking oral hormonal therapies as per recommended dosage and administration in the package insert. The remainder of the cohort had a hormone-eluting intrauterine device (IUD) placed. Despite these hormone therapies, VWD + HMB participants reported exceptionally high baseline PBAC scores (mean 1260 ± 136), well in excess of the clinical definition of heavy menstrual bleeding (PBAC > 100). Although this may not be representative of all women who have HMB, it represents a scenario in which hormone therapies may be insufficient in reducing menstrual blood loss. PBAC scores were reduced by >50%, a reduction equivalent to that seen with TXA (51). The HMBu cohort in this study, who were not on any form of hormone therapy, had significantly lower baseline PBAC scores than the VWD + HMB cohort (data not shown), which is not unexpected given the bleeding disorder in the latter cohort. Nonetheless, the HMBu cohort experienced a reduction in PBAC score similar in magnitude (>50%) as that observed in the VWD + HMB cohort. These observations suggest that the neural tourniquet pathway in humans is independent of von Willebrand factor, and activation of the pathway can improve hemostasis in the absence or presence of hormone therapy. Participants’ menstruations in both cohorts were ~1.5 days shorter while using tAN as compared with baseline menstruation, an effect not observed with TXA (52).

Participants in both cohorts in this study also experienced significant improvements in menstrual symptoms or health-related quality of life with the use of tAN. In the VWD + HMB cohort, use of tAN significantly improved severity and overall experience of menstrual symptoms on CMSS and improved several domains on the RAND-36. In contrast, use of tAN did not significantly change RAND-36 outcomes in the uHMB cohort, but the CMSS did reveal that use of tAN correlated with improvements in the frequency, severity and overall experience of menstrual symptoms as compared with baseline. A CMSS subdomain analysis revealed that pain is significantly reduced with the use of tAN. The effects of tAN on dysmenorrhea as measured by CMSS are similar to a prior study using transcutaneous auricular vagus nerve stimulation (taVNS) (27). In that study, participants received 30 min/day of taVNS at 1 Hz over 10 consecutive days between menstruations. The current study applied 60 min of tAN at 30 Hz to the ABVN (plus 100 Hz to the ATN) twice per day during menstruation. Wang et al. reported ~50% reduction in two menstruations following the use of taVNS, suggesting a persistence of effect on menstrual symptoms over time; the current study did not follow participants into subsequent menstruations. Moving forward, delivering tAN for consecutive cycles, during the luteal and menstrual phases, could demonstrate sustained or gradual improvements in menstrual symptoms. Thus, future treatment dosing studies are warranted.

Usability of the Volta device was rated favorably overall among participants in this study. Users did encounter some difficulty with the earpiece, in particular the inner electrode that is placed on the cymba concha to target the ABVN. The use of tAN during menstruation was safe over the duration of this study, with adverse events limited to minor skin irritation resulting from electrode placement in four of the participants. These observations are consistent with previous findings (31, 32). Transcutaneous auricular neurostimulation has an improved safety profile compared to implanted vagus nerve stimulators, which have been implanted in over 125,000 worldwide since the 1990s. Unlike implanted VNS, which have acute side effects during the “on” phase of stimulation such as cough, hoarseness, voice alteration, and paresthesia, tAN has minimal side effects due to its non-invasive nature (25). The Volta earpiece design with hydrogel electrodes minimizes skin irritation and discomfort and improves current distribution. Notably, no adverse events related to thrombosis have been reported in studies of cranial nerve stimulation, including implanted VNS devices. Indeed, an implanted VNS system was recently approved by the FDA to reduce upper extremity motor deficits and improve motor function during rehabilitation therapy in chronic ischemic stroke patients, a population that may be at increased risk of thrombotic events (53). The non-invasive nature of tAN overcomes many of the shortcomings of traditional VNS systems, including the expense and risks associated with surgical implantation (54).

The mechanism of tAN modulating hemostasis in humans has not been fully elucidated, however the results align with the prior preclinical studies (9, 10). In murine models of soft tissue injury vagus nerve stimulation (VNS) reduces blood loss; including mice deficient in coagulation factor VIII, a genetic deficiency similar to hemophilia A. VNS shortens the reaction (R) time on thromboelastography (TEG) and increases production of thrombin/anti-thrombin in blood shed from the wound (but not systemically) (9). VNS induces the release of acetylcholine in the spleen, which binds platelet acetylcholine receptors and triggers an influx of calcium. Platelets “primed” with elevated calcium levels are more responsive to pro-coagulant triggers at an “injury site” and have a greater increase of P selectin surface expression as compared with platelets from VNS-naïve mice (10). A recent randomized, sham-controlled, double-blinded study of tAN and taVNS in healthy human subjects suggests that transcutaneous neuromodulation strategies can improve laboratory hemostasis in humans (33, 34). Blood samples collected from subjects in this study revealed decreased R time and increased clot firmness as measured by the maximum amplitude parameter after stimulation as compared with sham. Platelet surface marker expression was measured by flow cytometry after ex vivo activation with platelet agonists; following stimulation, platelets responded to thrombin with increased surface expression of P selectin, while adenosine diphosphate (ADP) increased expression of glycoprotein IIb/IIIa compared with sham (33–34). Whether these changes occur in women with HMB, with or without VWD, requires further study.

Preclinical studies that have demonstrated VNS-induced improvements in hemostasis have leveraged devices that apply electrodes directly to the cervical vagus nerve, activating signals to the spleen that release acetylcholine and prime platelets (10). In this study, we used a transcutaneous approach to activate the vagus and trigeminal nerves on and around the ear. Stimulation of the auricular branch of the vagus nerve elicits responses in regions of the nucleus tractus solitarii (NTS) that are associated with cardiovagal outflow (55). The NTS is also associated with the regulation of other peripheral organs, including the spleen and immune system (54, 56). The neuroanatomical connection between cranial nerves around the human ear and platelets is not known; we hypothesize that tAN activates afferent signals to the NTS, which then activates efferent vagus nerve signals to the spleen via the splenic nerve (22, 57, 58).

The current study is not without limitations that should be addressed in future studies. A sample size of 8 per cohort is generally regarded as relatively small as compared with pharmaceutical studies. Subjects were followed for only one baseline menstrual episode, compared with 2–3 episodes in most trials (51), and use of concomitant therapies was heterogenous. Assessment of the underlying etiology of HMB and diagnosis of von Willebrand disease were not confirmed with medical chart reviews or direct testing methods. This was an open label study with baseline measurements taken during one menstruation before using the device and then in following menstruation with the use of tAN. As a pilot investigation, the design allowed for preliminary evaluation of both treatment effect and safety profile of a novel therapy, but the absence of a proper control group limits the ability to distinguish true therapeutic benefit from placebo effect or natural variability. The short duration of the study was an additional limitation, as was lack of bloodwork to directly assess the effects of tAN on hemostasis in these populations. Future studies should include larger sample sizes, blinded and sham-controlled arms, treatment during multiple consecutive menstruations, stratification by bleeding etiology, and incorporation of laboratory-based assessments of coagulation and platelet function.

This is the first study demonstrating use of a transcutaneous auricular neurostimulator during menstruation is associated with decreased menstrual blood loss among those with and without underlying bleeding disorder, including those using adjunct hormonal therapies. Across all study participants, tAN was safe, well-tolerated, and delivered clinically meaningful reductions in menstrual blood loss, menstrual symptoms, and quality of life. tAN activates the vagal and trigeminal networks which are hypothesized to modulate platelet phenotype and lead to improved hemostasis. This treatment modality offers a potential alternative to medications or surgery for women with HMB. A future FDA pivotal trial will be required to demonstrate safety and efficacy of tAN to treat HMB. Additional studies of tAN as a non-pharmaceutical, non-invasive approach to improve hemostasis in other bleeding disorders, as well as in surgery and trauma, are ongoing.