SheVari4(®), a proprietary root extract from Asparagus racemosus, ameliorates menopausal health: insights from a randomized, double-blind, placebo controlled clinical trial.

Anxiety disorders are among the most prevalent psychiatric conditions worldwide and impose a substantial individual and societal burden (). Clinically, anxiety disorders are frequently accompanied by somatic complaints, autonomic dysregulation, sleep disturbance, and endocrine abnormalities (; ; ; ). Epidemiological studies consistently demonstrate a marked sex bias in anxiety-related disorders, with women exhibiting greater vulnerability to stress (; ). In parallel, psychological stress is associated with menstrual irregularity and altered cycle length in women (; ; ; ), suggesting potentially shared neurobiological substrates underlying stress-related affective disorders and reproductive dysfunction. Rodent estrous cyclicity provides a tractable experimental readout of this neuroendocrine regulation. Vaginal cytology enables reliable classification of proestrus, estrus, metestrus, and diestrus based on cellular composition (; ; ; ). Deviations from the ordered sequence of these stages, including prolonged phase occupancy, abnormal transitions, altered estrus or diestrus duration, and reduced cycle regularity, are widely interpreted as indicators of disrupted estrous cyclicity (; ). However, while stress-induced hypothalamic-pituitary-gonadal (HPG) axis suppression has been extensively studied, the upstream limbic circuits that couple chronic stress exposure to both anxiety-like behaviors and estrous cycle dysfunction remain incompletely defined. The bed nucleus of the stria terminalis (BNST), a key component of the central extended amygdala, is well positioned to mediate such coupling. The BNST is critically involved in sustained anxiety states, diffuse threat processing, and stress integration (; ; ). Human neuroimaging studies further implicate the BNST in anxiety- and addiction-related disorders (). Importantly, the BNST exhibits marked cellular and functional heterogeneity, with distinct neuronal populations exerting divergent effects on behavior (; ; ). Circuit studies have shown that specific BNST pathways regulate anxiety-related behaviors in a projection- and neurotransmitter-specific manner (; ; ; ). Moreover, stress-responsive neuropeptide systems, including corticotropin-releasing hormone (CRH) and neuropeptide Y, modulate BNST synaptic transmission and contribute to anxiety and stress resilience (; ). Recent studies have identified BNST neuronal populations, including CRH- and protein kinase C delta (PKCδ)-expressing neurons, that are selectively recruited by aversive conditions to promote anxiety-like behaviors, particularly in females (; ). These findings underscore the need to define additional genetically specified BNST populations that may shape anxiety-like behavioral output during stress. Beyond its established role in anxiety, the BNST is also positioned to influence reproductive neuroendocrine regulation. Prior work has shown that BNST projections provide input to gonadotropin-releasing hormone (GnRH) cells () and that intra-BNST infusion of CRH can alter pulsatile luteinizing-hormone secretion (), suggesting that this extended-amygdala region may provide an upstream limbic route through which stress affects HPG-axis-related outcomes. In the present study, vaginal cytology is used as an integrated readout of estrous-cycle organization.