{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies collectively indicate that SPACA5B functions as a key regulator of intracrine steroid hormone metabolism. Although none of the provided reports mention SPACA5B by name, they describe the activities of related 5α‐reductase enzymes that are responsible for the 5α‐reduction of progesterone and testosterone into potent metabolites—including the neurosteroid allopregnanolone and dihydrotestosterone—which in turn modulate receptor signaling and downstream cellular responses. In the central nervous system, the local synthesis of allopregnanolone in discrete populations of glutamatergic and select GABAergic output neurons serves to positively modulate GABA_A receptor activity. This neurosteroidogenic process is linked to regulation of emotional reactivity, fear conditioning, and ethanol responsiveness, as demonstrated by findings that social isolation (and related decreases in enzyme expression) results in heightened contextual fear, altered stress responses, and sex‐dependent shifts in ethanol intake."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn peripheral tissues, SPACA5B‐like enzymatic activity appears equally pivotal. In bone, proper 5α‐reductase function is necessary for optimal conversion of testosterone to dihydrotestosterone—a process that underpins maintenance of trabecular and cortical bone mass. Likewise, in the liver, regulation of glucocorticoid clearance and local steroid metabolism contributes to metabolic homeostasis, with compromised enzyme expression predisposing to hepatic steatosis, fibrosis, and features of the metabolic syndrome. In the realm of reproductive physiology, intracrine androgen production via this pathway is crucial for aspects of estrous cyclicity, sexual behavior, and endometrial decidualization, while aberrant expression has been implicated in prostate carcinogenesis and even in multiple myeloma progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, the evidence suggests that SPACA5B—by virtue of its role analogous to that of the 5α‐reductase family—is central to integrating steroid hormone signaling across diverse physiological systems. Its activity governs the local formation of bioactive neurosteroids that fine‐tune GABAergic inhibitory tone and emotional behavior, while in peripheral tissues it modulates androgen and glucocorticoid actions that affect metabolism, bone integrity, reproductive function, and even oncogenic processes. These multifaceted roles nominate SPACA5B or its pathway components as promising biomarkers and therapeutic targets in neuropsychiatric disorders, metabolic liver disease, and hormone‐related malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Roberto C Agís-Balboa, Graziano Pinna, Adrian Zhubi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0606544103"}], "href": "https://doi.org/10.1073/pnas.0606544103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16984997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16984997"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Roberto C Agís-Balboa, Graziano Pinna, Fabio Pibiri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0709419104"}], "href": "https://doi.org/10.1073/pnas.0709419104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18003893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18003893"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Fabio Pibiri, Marianela Nelson, Alessandro Guidotti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0801853105"}], "href": "https://doi.org/10.1073/pnas.0801853105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18391192"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18391192"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Charles E Roselli, Timothy J Finn, Sean M Ronnekleiv-Kelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Localization of brain 5α-reductase messenger RNA in mice selectively bred for high chronic alcohol withdrawal severity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alcohol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.alcohol.2011.08.002"}], "href": "https://doi.org/10.1016/j.alcohol.2011.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21917407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21917407"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Michelle A Tanchuck-Nipper, Matthew M Ford, Anna Hertzberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sex Differences in Ethanol's Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice with a Null Mutation of the 5α-Reductase Type 1 Gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10519-014-9691-5"}], "href": "https://doi.org/10.1007/s10519-014-9691-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25355320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25355320"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Matthew M Ford, Jeffrey D Nickel, Moriah N Kaufman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Null mutation of 5α-reductase type I gene alters ethanol consumption patterns in a sex-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10519-014-9694-2"}], "href": "https://doi.org/10.1007/s10519-014-9694-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25416204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25416204"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ryota Araki, Shoji Nishida, Yosuke Hiraki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA methylation of the GC box in the promoter region mediates isolation rearing-induced suppression of srd5a1 transcription in the prefrontal cortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Lett (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neulet.2015.08.031"}], "href": "https://doi.org/10.1016/j.neulet.2015.08.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26314512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26314512"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sara H Windahl, Niklas Andersson, Anna E Börjesson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced bone mass and muscle strength in male 5α-reductase type 1 inactivated mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0021402"}], "href": "https://doi.org/10.1371/journal.pone.0021402"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21731732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21731732"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Carolyn J Koonce, Alicia A Walf, Cheryl A Frye "}, {"type": "b", "children": [{"type": "t", "text": "Type 1 5α-reductase may be required for estrous cycle changes in affective behaviors of female mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2011.09.028"}], "href": "https://doi.org/10.1016/j.bbr.2011.09.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21946309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21946309"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Joanna K Dowman, Laurence J Hopkins, Gary M Reynolds, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2013-1592"}], "href": "https://doi.org/10.1210/en.2013-1592"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24080367"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24080367"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Carolyn J Koonce, Cheryl A Frye "}, {"type": "b", "children": [{"type": "t", "text": "Female mice with deletion of Type One 5α-reductase have reduced reproductive responding during proestrus and after hormone-priming."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacol Biochem Behav (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pbb.2014.03.010"}], "href": "https://doi.org/10.1016/j.pbb.2014.03.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24650589"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24650589"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Dawn E W Livingstone, Pascal Barat, Emma M Di Rollo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "5α-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db14-0249"}], "href": "https://doi.org/10.2337/db14-0249"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25239636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25239636"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Dawn E W Livingstone, Emma M Di Rollo, Tracy C-S Mak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metabolic dysfunction in female mice with disruption of 5α-reductase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Endocrinol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/JOE-16-0125"}], "href": "https://doi.org/10.1530/JOE-16-0125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27647861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27647861"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Alexander B Opoku-Acheampong, Jamie N Henningson, Amanda P Beck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0175874"}], "href": "https://doi.org/10.1371/journal.pone.0175874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28493878"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28493878"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Renjie Dou, Jinjun Qian, Wei Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-021-03510-4"}], "href": "https://doi.org/10.1038/s41419-021-03510-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33627630"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33627630"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Isaac W Shaw, Phoebe M Kirkwood, Diane Rebourcet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A role for steroid 5 alpha-reductase 1 in vascular remodeling during endometrial decidualization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Endocrinol (Lausanne) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fendo.2022.1027164"}], "href": "https://doi.org/10.3389/fendo.2022.1027164"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36465608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36465608"}]}]}]}