{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nLuteinizing hormone (LH)–β, the unique subunit of this heterodimeric glycoprotein hormone, is essential for normal reproductive development and function. Genetic models that eliminate LH–β expression produce mice with markedly impaired gonadal growth, defective steroidogenesis, and infertility, while naturally occurring mutations in the LHB gene disrupt mRNA splicing or protein secretion, resulting in clinical presentations ranging from hypogonadism and delayed puberty in males to ovulatory failure, menstrual irregularities, and infertility in females. These human studies underscore that appropriate synthesis and secretion of the LH–β subunit are indispensable for gonadal steroid production and gametogenesis."}, {"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": "\nBeyond its critical role in reproductive physiology, precise structural features and transcriptional regulation of the LH–β subunit determine its secretion dynamics and functional bioactivity. The carboxyl-terminal domain of LH–β contains specific amino acid motifs that direct the hormone into the regulated (basolateral) secretory pathway, while single nucleotide polymorphisms (including the common Trp8Arg/Ile15Thr substitutions and other coding as well as promoter variants) modulate its half-life and receptor interaction without necessarily disrupting in vitro binding. Moreover, transcription factors and co-regulators such as FOXO1—and even accessory proteins like MIP-2A—have been implicated in fine-tuning LHB gene expression in gonadotropes, helping to integrate metabolic signals with reproductive output. These structural and regulatory insights help explain the variable ovarian responses (e.g. altered sensitivity to exogenous FSH in in vitro fertilization protocols) observed in carriers of variant LH (v‐LH) alleles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further indicates that variations in LHB and its downstream effects may extend beyond classical reproductive endpoints. Elevated LH levels—often a consequence of altered LHB gene function—have been linked with neurodegenerative processes such as amyloid‐β deposition in Alzheimer’s disease, as well as with changes in bone metabolism and even vascular pathophysiology. Additionally, polymorphisms in LHB (and in concert with LH receptor gene variations) are associated with conditions such as polycystic ovary syndrome and endometriosis, while altered LH dynamics have also been observed in metabolic disorders including diabetic kidney disease. Collectively, these findings illustrate that the LHB gene product not only serves as a key regulator of gonadal steroidogenesis and gametogenesis but may also influence extra‐gonadal processes through both endocrine and paracrine mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R Gazvani, P Pakarinen, P Fowler, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0404743101"}], "href": "https://doi.org/10.1073/pnas.0404743101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15569941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15569941"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Adriana Lofrano-Porto, Gustavo Barcelos Barra, Leonardo Abdala Giacomini, et al. 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