{"doi":"10.1111/apha.14094","title":"Keeping breathing in balance through hormonal modulation in respiratory control","abstract":"The neurophysiological control of breathing is a complex and dynamic process with consistent robustness from the first to the last breaths of life. However, this robustness is complemented by a flexibility that enables mammals to adjust breathing rapidly and precisely in line with ever-changing behavioral, hormonal, and metabolic demands. A clear example of this flexibility is the ability of the respiratory control system to alter breathing in response to changes in oxygen and carbon dioxide. When oxygen or carbon dioxide levels change, alveolar ventilation adjusts to maintain homeostasis.1 These responses, termed chemoreflexes, support metabolic demands, acid–base balance, hemodynamic responses,2 and other essential neurophysiological functions. Disorders like sleep apnea, congenital central hypoventilation syndrome (CCHS), and obesity hypoventilation syndrome, which disrupt these reflexes, often have dire consequences, such as increased mortality risk and associated conditions including hypertension3 and heart failure. Within this complex interplay of neurophysiology, an emerging area of research has spotlighted the influence of hormones, specifically progesterone, on respiratory control. In this issue of Acta Physiologica, Janes and Cardani et al. dive into this area, presenting work on the role of the progesterone-like drug etonogestrel (ETO) in modulating the CO2 chemoreflex and offering new insights into potential therapeutic interventions for respiratory disorders (JANES REF). While the concept of chemoreflexes is simple, the molecular mechanisms giving rise to chemosensitivity are far from straightforward. Multiple interconnected peripheral and neural networks constantly send and receive electrochemical signals that culminate to drive respiratory motor discharge. Additionally, superimposed onto these networks is a constant bombardment of hormonal and other neuromodulatory signals that influence the reactivity and recruitment of all networks involved in the control of breathing.4 Behaviorally, this can be evident by hyperventilation in response to stress, predominately driven by sympathetic excitatory drive, or during NREM sleep when control networks for ventilation display lower excitatory and greater inhibitory neuromodulatory influence, leading to lower ventilation compared to the awake state. Additionally, hormonal influences on the control of breathing are beginning to shed light on a complex system of neurohormonal modulators to modify breathing in accordance with fluctuations in local and circulating hormones. Hormonal modulation of breathing might seem intuitive given well-established associations, such as erythropoietin (EPO) release in response to hypoxemia5 and glucocorticoid-driven changes in metabolic rate. However, the influence of sex hormones on breathing remain heavily debated and controversial. In relation to the current report by Janes and Cardini et al., the influence of the sex hormone progesterone on breathing has produced important but inconsistent reports throughout the literature. Progesterone has widely been suggested to act as a respiratory stimulant,6 with ample evidence showing its efficacy for increasing chemosensitivity. However, the conditions that result in progesterone-stimulated breathing show variability that call into question the state-dependent influence of progesterone on respiratory control. For example, women with lower levels of estradiol and/or progesterone have been shown to display a higher incidence of sleep disordered breathing compared to age, menstrual cycle, and post-menopausal matched women. However, certain studies of conditions accompanied by higher levels of estradiol and/or progesterone, such as pregnancy, show a higher incidence of sleep disordered breathing, despite the supposed stimulatory effects of the hormones. Nonetheless, this contradictory evidence further strengthens the idea that hormonal influence over respiration may be an important factor under varyin","journal":"Acta Physiologica","year":2024,"id":493399,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":634616,"name":"Nicholas J. Burgraff","orcid":"0000-0001-7986-4247","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:09:03.883685Z","pmid":"38235961","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}