Keywords
Follicle-stimulating hormone
Bone
Periodontitis
Osteoporosis
Rheumatoid arthritis
Bone metastasis
How to Cite
Abstract
Context: Bones are highly dynamic organs that depend on constant and balanced remodeling to maintain their homeostasis. Bone tissue is sensitive to hormonal stimuli, which can influence bone remodeling processes and, in some cases, lead to imbalances that result in various bone-related diseases. Recent research has shown that bone cells are sensitive to follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which appear to affect bone remodeling in health and disease.
Objectives: To explore the roles of luteinizing hormone and follicle-stimulating hormone in bone remodeling and the development of systemic and alveolar bone diseases in males and females.
Methodology: A literature search was conducted in the PubMed and Google Scholar databases. We used the following keywords and their combinations as search criteria: FSH, LH, follicle-stimulating hormone, luteinizing hormone, bone remodeling, alveolar bone, periodontitis, arthritis, osteoporosis, bone metastasis, men, and women.
Results: Emerging evidence suggests that follicle-stimulating hormone and luteinizing hormone play a significant role in bone metabolism and actively contribute to bone diseases such as osteoporosis, rheumatoid arthritis, bone metastasis, and periodontitis through inflammatory and pro-apoptotic mechanisms and by modulating the differentiation and activity of osteoblasts and osteoclasts.
Conclusion: The increase in follicle-stimulating hormone and luteinizing hormone are associated with the development and severity of different bone diseases. These findings provide a fresh perspective on the relationship between bone health and gonadotropins. Modulation of gonadotropin levels may represent a good therapeutic target for the treatment of various systemic pathologies of the skeleton and oral cavity.
References
Veis DJ, O’Brien CA. Osteoclasts, master sculptors of bone. Annu Rev Pathol. 2023;18:257-281. https://doi.org/10.1146/annurev-pathmechdis-031521-040919
Kenkre JS, Bassett J. The bone remodelling cycle. Ann Clin Biochem. 2018;55(3):308-327. https://doi.org/10.1177/0004563218759371
Schlesinger PH, Blair HC, Stolz DB, Riazanski V, Ray EC, Tourkova IL, et al. Cellular and extracellular matrix of bone, with principles of synthesis and dependency of mineral deposition on cell membrane transport. Am J Physiol Cell Physiol. 2020;318(1):c111-c124. https://doi.org/10.1152/ajpcell.00120.2019
Taylor EA, Donnelly E, Yao X, Johnson ML, Amugongo SK, Kimmel DB, et al. Sequential treatment of estrogen deficient, osteopenic rats with alendronate, parathyroid hormone (1–34), or raloxifene alters cortical bone mineral and matrix composition. Calcif Tissue Int. 2020;106(3):303-314. https://doi.org/10.1007/s00223-019-00634-w
Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone turnover markers: Basic biology to clinical applications. Endocr Rev. 2023;44(3):417-473. https://doi.org/10.1210/endrev/bnac031
Maciel GBM, Maciel RM, Danesi CC. Bone cells and their role in physiological remodeling. Mol Biol Rep. 2023;50(3):2857-2863. https://doi.org/10.1007/s11033-022-08190-7
Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T, Uehara S, et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab. 2021;39(1):19-26. https://doi.org/10.1007/s00774-020-01162-6
Venken K, Callewaert F, Boonen S, Vanderschueren D. Sex hormones, their receptors and bone health. Osteoporos Int. 2008;19(11):1517-1525. https://doi.org/10.1007/s00198-008-0609-z
Bretherton I, Ghasem-Zadeh A, Leemaqz SY, Seeman E, Wang X, McFarlane T, et al. Bone microarchitecture in transgender adults: A cross-sectional study. J Bone Miner Res. 2022;37(4):643-648. https://doi.org/10.1002/jbmr.4497
Corona G, Vena W, Pizzocaro A, Giagiulli VA, Francomano D, Rastrelli G, et al. Testosterone supplementation and bone parameters: A systematic review and meta-analysis study. J Endocrinol Invest. 2022;45(5):911-926. https://doi.org/10.1007/s40618-021-01702-5
Nirrit-Esclassan E, Valera MC, Tremollieres F, Arnal JF, Lenfant F, Fontaine C, et al. Critical role of estrogens on bone homeostasis in both male and female: From physiology to medical implications. Int J Mol Sci. 2021;22(4):1568. https://doi.org/10.3390/ijms22041568
Russell N, Ghasem-Zadeh A, Hoermann R, Cheung AS, Zajac JD, Shore-Lorenti C, et al. Effects of estradiol on bone in men undergoing androgen deprivation therapy: A randomized placebo-controlled trial. Eur J Endocrinol. 2022;187(2):241-256. https://doi.org/10.1530/EJE-22-0227
Fuqua JS, Eugster EA. History of puberty: Normal and precocious. Horm Res Paediatr. 2022;95(6):568-578. https://doi.org/10.1159/000526464
Ji Y, Liu P, Yuen T, Haider S, He J, Romero R, et al. Epitope-specific monoclonal antibodies to FSH? increase bone mass. Proc Natl Acad Sci. 2018;115(9):2192-2197. https://doi.org/10.1073/pnas.1718144115
Gupta PK, Sheoran A, Gupta P, Kumar Mahto S, Jain P, Varshney A, et al. Association of sex hormones and androgens with disease activity in premenopausal females with rheumatoid arthritis. Mediterr J Rheumatol. 2023;34(2):152-158. https://doi.org/10.31138/mjr.34.2.152
Mansell JP, Bailey AJ, Yarram SJ. Could bone tissue be a target for luteinizing hormone/chorionic gonadotropin? Mol Cell Endocrinol. 2007;269. https://doi.org/10.1016/j.mce.2006.06.016
Wu XY, Wu XP, Luo XH, Xie H, Xhang H, Peng YQ, et al. The relationship between the levels of gonadotropic hormones and OPG, leptin, TGF-?1 and TGF-?2 in Chinese adult women. Clinica Chimica Acta. 2010;411(17-18):1296-1305. https://doi.org/10.1016/j.cca.2010.05.006
Wu M, Wu S, Chen W, Li YP. The roles and regulatory mechanisms of TGF-? and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res. 2024;34(2):101-123. https://doi.org/10.1038/s41422-023-00918-9
Erlebacher A, Derynck R. Increased expression of TGF-?2 in osteoblasts results in an osteoporosis-like phenotype. J Cell Biol. 1996;132(1):195-210. https://doi.org/10.1083/jcb.132.1.195
Fu S, Ping P, Li Y, Li B, Zhao Y, Yao Y, et al. Centenarian longevity had inverse relationships with nutritional status and abdominal obesity and positive relationships with sex hormones and bone turnover in the oldest females. J Transl Med. 2021;19(1):436. https://doi.org/10.1186/s12967-021-03115-7
Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, et al. FSH Directly regulates bone mass. Cell. 2006;125(2):247-260. https://doi.org/10.1016/j.cell.2006.01.051
Iqbal J, Sun L, Kumar TR, Blair HC, Zaidi M. Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci. 2006;103(40):14925-14930. https://doi.org/10.1073/pnas.0606805103
Sowers MR, Greendale GA, Bondarenko I, Kinkelstein JS, Cauley JS, Neer RM, et al. Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN. Osteoporos Int. 2003;14(3):191-197. https://doi.org/10.1007/s00198-002-1329-4
Sowers MFR, Jannausch M, McConnell D, Little R, Greendale GA, Finkelstein JS, et al. Hormone predictors of bone mineral density changes during the menopausal transition. J Clin Endocrinol Metab. 2006;91(4):1261-1267. https://doi.org/10.1210/jc.2005-1836
Devleta B, Adem B, Senada S. Hypergonadotropic amenorrhea and bone density: New approach to an old problem. J Bone Miner Metab. 2004;22(4):360-364. https://doi.org/10.1007/s00774-004-0495-1
Chrusciel M, Ponikwicka-Tyszko D, Wolczynski S, Huhtaniemi I, Rahman NA. Extragonadal FSHR expression and function-is it real? Front Endocrinol (Lausanne). 2019;10:32. https://doi.org/10.3389/fendo.2019.00032
Wu KC, Ewing SK, Li X, Sigurosson S, Guanason V, Kado DM, et al. FSH Level and changes in bone mass and body composition in older women and men. J Clin Endocrinol Metab. 2021;106(10):2876-2889. https://doi.org/10.1210/clinem/dgab481
Radu AF, Bungau SG. Management of rheumatoid arthritis: An overview. Cells. 2021;10(11):2857. https://doi.org/10.3390/cells10112857
Kåss AS, Lea TE, Torjesen PA, Gulseth HC, Førre T. The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: A casecontrol study. Scand J Rheumatol. 2010;39(2):109-117. https://doi.org/10.3109/03009740903270607
Takeuchi T, Tanaka Y, Higashitani C, Iwai M, Komatsu K, Akazawa R, et al. A phase 2a, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral gonadotropin-releasing hormone antagonist, ASP1707, in postmenopausal female patients with rheumatoid arthritis taking methotrexate. Mod Rheumatol. 2021;31(1):53-60. https://doi.org/10.1080/14397595.2020.1733214
Kyaw MT, Sakthiswary R, Ani Amelia Z, Rahana AR, Munirah MM. Effects of methotrexate therapy on the levels of gonadotropic hormones in rheumatoid arthritis patients of reproductive age. Cureus. 2020;12(4):e7632. https://doi.org/10.7759/cureus.7632
Turmuhambetova BT, Kozlova LK, Dzhulamanova AB, Nikonova EN. The features of reproductive function in women with rheumatoid arthritis. Vrach. 2020;31(5):18-22. https://doi.org/10.29296/25877305-2020-05-04
Kong D, Guan Q, Li G, Xin W, Qi X, Guo Y, et al. Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes. Biochem Biophys Res Commun. 2018;495(1):587-593. https://doi.org/10.1016/j.bbrc.2017.11.053
Wang Y, Zhang M, Huan Z, Shao S, Zhang X, Kong D, et al. FSH directly regulates chondrocyte dedifferentiation and cartilage development. J Endocrinol. 2021;248(2):193-206. https://doi.org/10.1530/JOE-20-0390
Zhang M, Wang Y, Huan Z, Liu Y, Zhang W, Kong D, et al. FSH modulated cartilage ECM metabolism by targeting the PKA/CREB/SOX9 pathway. J Bone Miner Metab. 2021;39(5):769-779. https://doi.org/10.1007/s00774-021-01232-3
Zhang X, Qiao P, Guo Q, Liang Z, Pan J, Wu F, et al. High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front Endocrinol (Lausanne). 2022;13:862849. https://doi.org/10.3389/fendo.2022.862849
Belenska-Todorova L, Zhivkova R, Markova M, Ivanovska N. Follicle stimulating hormone and estradiol alter immune response in osteoarthritic mice in an opposite manner. Int J Immunopathol Pharmacol. 2021;35. https://doi.org/10.1177/20587384211016198
Wu D, Cline-Smith A, Shashkova E, Perla A, Katyal A, Aurora R. T-cell mediated inflammation in postmenopausal osteoporosis. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.687551
Yarram SJ, Perry MJ, Christopher TJ, Westby K, Brown NL, Lamminen T, et al. Luteinizing hormone receptor knockout (LuRKO) mice and transgenic human chorionic gonadotropin (hCG)-overexpressing mice (hCG ??+) have bone phenotypes. Endocrinology. 2003;144(8):3555-3564. https://doi.org/10.1210/en.2003-0036
Xu ZR, Wang AH, Wu XP, Zhang H, Sheng ZF, Wu XY, et al. Relationship of age-related concentrations of serum FSH and LH with bone mineral density, prevalence of osteoporosis in native Chinese women. Clinica Chimica Acta. 2009;400(1-2). https://doi.org/10.1016/j.cca.2008.09.027
Lkhagvasuren U, Jav S, Zagdsuren B. Correlation between reproductive hormonal level and osteoporosis among women in Mongolia. Cent Asian J Glob Health. 2016;4(2). https://doi.org/10.5195/cajgh.2015.239
Hsu B, Cumming RG, Seibel MJ, Naganathan V, Blyth FM, Bleicher K, et al. Reproductive hormones and longitudinal change in bone mineral density and incident fracture risk in older men: The concord health and aging in men project. J Bone Miner Res. 2015;30(9):1701-1708. https://doi.org/10.1002/jbmr.2493
Peters JL, Fairney A, Kyd P, Patel A, Rogers S, Webster JJ, et al. Bone loss associated with the use of LHRH agonists in prostate cancer. Prostate Cancer Prostatic Dis. 2001;4(3):161-166. https://doi.org/10.1038/sj.pcan.4500520
Zaidi M, New MI, Blair HC, Zallone A, Baliram R, Davies TF, et al. Actions of pituitary hormones beyond traditional targets. J Endocrinol. 2018;237(3):R83-R98. https://doi.org/10.1530/JOE-17-0680
Rendina D, Gianfrancesco F, De Filippo G, Merlotti D, Esposito T, Mingione A, et al. FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. Eur J Endocrinol. 2010;163(1):165-172. https://doi.org/10.1530/EJE-10-0043
Gera S, Kuo TC, Gumerova AA, Korkmaz F, Sant D, DeMambro V, et al. FSH-blocking therapeutic for osteoporosis. Elife. 2022;11:e78022. https://doi.org/10.7554/eLife.78022
Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, Dhawan S, et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017;546(7656):107-112. https://doi.org/10.1038/nature22342
Gera S, Sant D, Haider S, Korkmaz F, Kuo TC, Mathew M, et al. First-in-class humanized FSH blocking antibody targets bone and fat. Proc Natl Acad Sci. 2020;117(46):28971-28979. https://doi.org/10.1073/pnas.2014588117
Zhu LL, Blair H, Cao J, Yuen T, Latif R, Guo L, et al. Blocking antibody to the ?-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proc Natl Acad Sci. 2012;109(36):14574-14579. https://doi.org/10.1073/pnas.1212806109
Jayarangaiah A, Kemp AK, Theetha Kariyanna P. Bone Metastasis. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507911/
Min GE, Ahn H. Conversion to monotherapy with luteinizing-hormone releasing hormone agonist or orchiectomy after reaching PSA nadir following maximal androgen blockade is able to prolong progression-free survival in patients with metastatic prostate cancer: A propensity score matching analysis. Oncol Lett. 2017;13(6):4832-4836. https://doi.org/10.3892/ol.2017.6056
Nishimura R, Anan K, Yamamoto Y, Higaki K, Tanaka M, Shibuta K, et al. Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with tamoxifen: Results of the JMTO BC08-01 phase II trial. Oncol Rep. 2013;29(5):1707-1713. https://doi.org/10.3892/or.2013.2312
Klijn JGM, Blamey RW, Boccardo F, Tominaga T, Duchteau L, Sylvester R, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol. 2001;19(2):343-353. https://doi.org/10.1200/JCO.2001.19.2.343
Schubert A, Hawighorst T, Emons G, Gründker C. Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo. Breast Cancer Res Treat. 2011;130(3):783-790. https://doi.org/10.1007/s10549-011-1358-9
Schally AV, Comaru-Schally AM. Mode of action of LHRH analogs. In: Bast RC, Kufe DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E, editors. Holland-Frei Cancer Medicine. 6th ed. Hamilton (ON): BC Decker; 2003.
Crawford ED, Schally AV, Pinthus JH, Block NL, Rick FG, Garnick MB, et al. The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy. Urol Oncol. 2017;35(5):183-191. https://doi.org/10.1016/j.urolonc.2017.01.025
Cannon JG, Kraj B, Sloan G. Follicle-stimulating hormone promotes RANK expression on human monocytes. Cytokine. 2011;53(2):141-144. https://doi.org/10.1016/j.cyto.2010.11.011
Zheng Y, Basel D, Chow SO, Fong-Yee C, Kim S, Buttgereit F, et al. Targeting IL-6 and RANKL signaling inhibits prostate cancer growth in bone. Clin Exp Metastasis. 2014;31(8):921-933. https://doi.org/10.1007/s10585-014-9680-3
Schröder FH, Tombal B, Miller K, Boccon-Gibod L, Shore ND, Crawford ED, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: Results from a 12-month, comparative, phase III study. BJU Int. 2010;106(2):182-187. https://doi.org/10.1111/j.1464-410X.2009.08981.x
Siraj A, Desestret V, Antoine M, Fromont G, Huerre M, Sanson M, et al. Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases. BMC Cancer. 2013;13:246. https://doi.org/10.1186/1471-2407-13-246
Deivaraju C, Temple HT, Block N, Robinson P, Schally AV. LHRH receptor expression in sarcomas of bone and soft tissue. Horm Mol Biol Clin Investig. 2016;28(2):105-111. https://doi.org/10.1515/hmbci-2016-0001
Trindade D, Carvalho R, Machado V, Chambrone L, Mendes JJ, Botelho J. Prevalence of periodontitis in dentate people between 2011 and 2020: A systematic review and meta-analysis of epidemiological studies. J Clin Periodontol. 2023;50(5):604-626. https://doi.org/10.1111/jcpe.13769
Hu D, Zhang F, Li H, Xu X, Wen P, Zheng Z, et al. Polycystic ovary syndrome is positively correlated with periodontitis: A prospective study. J South Med Univ. 2024;44(1):36-44. https://doi.org/10.12122/j.issn.1673-4254.2024.01.05
Liu S, Cheng Y, Xu W, Bian Z. Protective effects of follicle-stimulating hormone inhibitor on alveolar bone loss resulting from experimental periapical lesions in ovariectomized rats. J Endod. 2010;36(4):658-663. https://doi.org/10.1016/j.joen.2010.01.011
Mills EG, Yang L, Nielsen MF, Kassem M, Dhillo WS, Comninos AN. The relationship between bone and reproductive hormones beyond estrogens and androgens. Endocr Rev. 2021;42(6):691-719. https://doi.org/10.1210/endrev/bnab015
Liu S, Cheng Y, Fan M, Chen D, Bian Z. FSH aggravates periodontitis-related bone loss in ovariectomized rats. J Dent Res. 2010;89(4):366-371. https://doi.org/10.1177/0022034509358822
Qian H, Guan X, Bian Z. FSH aggravates bone loss in ovariectomised rats with experimental periapical periodontitis. Mol Med Rep. 2016;14(4):2997-3006. https://doi.org/10.3892/mmr.2016.5613
Zhu C, Ji Y, Liu S, Bian Z. Follicle-stimulating hormone enhances alveolar bone resorption via upregulation of cyclooxygenase-2. Am J Transl Res. 2016;8(9):3861-3871.
Qian H, Jia J, Yang Y, Bian Z, Ji Y. A follicle-stimulating hormone exacerbates the progression of periapical inflammation through modulating the cytokine release in periodontal tissue. Inflammation. 2020;43(4):1572-1585. https://doi.org/10.1007/s10753-020-01234-9
Haytaç MC, Cetin T, Seydaoglu G. The effects of ovulation induction during infertility treatment on gingival inflammation. J Periodontol. 2004;75(6):805-810. https://doi.org/10.1902/jop.2004.75.6.805
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