Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

INSL3: A Marker of Leydig Cell Function and Testis-Bone-Skeletal Muscle Network

Author(s): Paolo Facondo, Andrea Delbarba, Filippo Maffezzoni, Carlo Cappelli and Alberto Ferlin*

Volume 27, Issue 12, 2020

Page: [1246 - 1252] Pages: 7

DOI: 10.2174/0929866527666200925105739

Price: $65

Abstract

This article reviews the role of INSL3 as biomarker of Leydig cell function and its systemic action in testis-bone-skeletal muscle crosstalk in adult men. Insulin-like factor 3 (INSL3) is a peptide hormone secreted constitutively in a differentiation-dependent mode by testicular Leydig cells. Besides the role for the testicular descent, this hormone has endocrine anabolic functions on the bone-skeletal muscle unit. INSL3 levels are low in many conditions of undifferentiated or altered Leydig cell status, however the potential clinical utility of INSL3 measurement is not yet well defined. INSL3 levels are modulated by the long-term cytotropic effect of the hypothalamicpituitary- gonadal axis, unlike testosterone that is acutely sensitive to the stimulus by luteinizing hormone (LH). INSL3 directly depends on the number and differentiation state of Leydig cells and therefore it represents the ideal marker of Leydig cell function. This hormone is more sensitive than testosterone to Leydig cell impairment, and the reduction of INSL3 in adult men can precociously detect an endocrine testicular dysfunction. Low INSL3 levels could cause or contribute to some symptoms and signs of male hypogonadism, above all sarcopenia and osteoporosis. The measurement provided suggested that the measurement of INSL3 levels should be considered in the clinical management of male hypogonadism and in the evaluation of testicular endocrine function. The monitoring of INSL3 levels could allow an early detection of Leydig cell damage, even when testosterone levels are still in the normal range.

Keywords: Insulin-like factor 3 (INSL3), leydig, testis-bone-muscle crosstalk, hypogonadism, testosterone, osteoporosis, sarcopenia.

« Previous Next »
Graphical Abstract

[1]
Ivell, R.; Wade, J.D.; Anand-Ivell, R. INSL3 as a biomarker of leydig cell functionality. Minireview. Biol. Reprod., 2013, 88(6), 1-8.
[http://dx.doi.org/10.1095/biolreprod.113.108969]
[2]
Bay, K.; Andersson, A.M. Human testicular insulin-like factor 3: In relation to development, reproductive hormones and andrological disorders. Int. J. Androl., 2011, 34(2), 97-109.
[http://dx.doi.org/10.1111/j.1365-2605.2010.01074.x] [PMID: 20550598]
[3]
Foresta, C.; Bettella, A.; Vinanzi, C.; Dabrilli, P.; Meriggiola, M.C.; Garolla, A.; Ferlin, A. A novel circulating hormone of testis origin in humans. J. Clin. Endocrinol. Metab., 2004, 89(12), 5952-5958.
[http://dx.doi.org/10.1210/jc.2004-0575] [PMID: 15579743]
[4]
Sansone, A.; Kliesch, S.; Isidori, A.M.; Schlatt, S. AMH and INSL3 in testicular and extragonadal pathophysiology: What do we know? Andrology, 2019, 7(2), 131-138.
[http://dx.doi.org/10.1111/andr.12597] [PMID: 30793542]
[5]
O’Shaughnessy, P.J.; Baker, P.J.; Monteiro, A.; Cassie, S.; Bhattacharya, S.; Fowler, P.A. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J. Clin. Endocrinol. Metab., 2007, 92(12), 4792-4801.
[http://dx.doi.org/10.1210/jc.2007-1690] [PMID: 17848411]
[6]
Harrison, S.M.; Bush, N.C.; Wang, Y.; Mucher, Z.R.; Lorenzo, A.J.; Grimsby, G.M.; Schlomer, B.J.; Büllesbach, E.E.; Baker, L.A. Insulin-Like Peptide 3 (INSL3) serum concentration during human male fetal life. Front. Endocrinol. (Lausanne), 2019, 10, 596.
[http://dx.doi.org/10.3389/fendo.2019.00596] [PMID: 31611843]
[7]
Anand-Ivell, R.; Ivell, R.; Driscoll, D.; Manson, J. Insulin-like factor 3 levels in amniotic fluid of human male fetuses. Hum. Reprod., 2008, 23(5), 1180-1186.
[http://dx.doi.org/10.1093/humrep/den038] [PMID: 18310050]
[8]
Ferlin, A.; Garolla, A.; Rigon, F.; Rasi Caldogno, L.; Lenzi, A.; Foresta, C. Changes in serum insulin-like factor 3 during normal male puberty. J. Clin. Endocrinol. Metab., 2006, 91(9), 3426-3431.
[http://dx.doi.org/10.1210/jc.2006-0821] [PMID: 16804040]
[9]
Anand-Ivell, R.; Wohlgemuth, J.; Haren, M.T.; Hope, P.J.; Hatzinikolas, G.; Wittert, G.; Ivell, R. Peripheral INSL3 concentrations decline with age in a large population of Australian men. Int. J. Androl., 2006, 29(6), 618-626.
[http://dx.doi.org/10.1111/j.1365-2605.2006.00714.x] [PMID: 17014531]
[10]
Ivell, R.; Anand-Ivell, R. Biological role and clinical significance of insulin-like peptide 3. Curr. Opin. Endocrinol. Diabetes Obes., 2011, 18(3), 210-216.
[http://dx.doi.org/10.1097/MED.0b013e3283453fe6] [PMID: 21415739]
[11]
Anand-Ivell, R.J.; Relan, V.; Balvers, M.; Coiffec-Dorval, I.; Fritsch, M.; Bathgate, R.A.; Ivell, R. Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biol. Reprod., 2006, 74(5), 945-953.
[http://dx.doi.org/10.1095/biolreprod.105.048165] [PMID: 16467492]
[12]
Kawamura, K.; Kumagai, J.; Sudo, S.; Chun, S.Y.; Pisarska, M.; Morita, H.; Toppari, J.; Fu, P.; Wade, J.D.; Bathgate, R.A.; Hsueh, A.J. Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc. Natl. Acad. Sci. USA, 2004, 101(19), 7323-7328.
[http://dx.doi.org/10.1073/pnas.0307061101] [PMID: 15123806]
[13]
Del Borgo, M.P.; Hughes, R.A.; Bathgate, R.A.; Lin, F.; Kawamura, K.; Wade, J.D. Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J. Biol. Chem., 2006, 281(19), 13068-13074.
[http://dx.doi.org/10.1074/jbc.M600472200] [PMID: 16547350]
[14]
Shokri, S.; Tavalaee, M.; Ebrahimi, S.M.; Ziaeipour, S.; Nasr-Esfahani, M.H.; Nejatbakhsh, R. Expression of RXFP2 receptor on human spermatozoa and the anti-apoptotic and antioxidant effects of insulin-like factor 3. Andrologia, 2020, 59(9), e13715.
[http://dx.doi.org/10.1111/ and.13715] [PMID: 32557760]
[15]
De Toni, L.; Agoulnik, A.I.; Sandri, M.; Foresta, C.; Ferlin, A. INSL3 in the muscolo-skeletal system. Mol. Cell. Endocrinol., 2019, 487, 12-17.
[http://dx.doi.org/10.1016/j.mce.2018.12.021] [PMID: 30625346]
[16]
Ferlin, A.; Selice, R.; Carraro, U.; Foresta, C. Testicular function and bone metabolism-beyond testosterone. Nat. Rev. Endocrinol., 2013, 9(9), 548-554.
[http://dx.doi.org/10.1038/nrendo.2013.135] [PMID: 23856820]
[17]
Fu, P.; Shen, P.J.; Zhao, C.X.; Scott, D.J.; Samuel, C.S.; Wade, J.D.; Tregear, G.W.; Bathgate, R.A.D.; Gundlach, A.L. Leucine-rich repeat-containing G-protein-coupled receptor 8 in mature glomeruli of developing and adult rat kidney and inhibition by insulin-like peptide-3 of glomerular cell proliferation. J. Endocrinol., 2006, 189(2), 397-408.
[http://dx.doi.org/10.1677/joe.1.06697] [PMID: 16648305]
[18]
Sedaghat, K.; Shen, P.J.; Finkelstein, D.I.; Henderson, J.M.; Gundlach, A.L. Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections. Neuroscience, 2008, 156(2), 319-333.
[http://dx.doi.org/10.1016/j.neuroscience.2008.07.029] [PMID: 18706979]
[19]
Hombach-Klonisch, S.; Bialek, J.; Radestock, Y.; Truong, A.; Agoulnik, A.I.; Fiebig, B.; Willing, C.; Weber, E.; Hoang-Vu, C.; Klonisch, T. INSL3 has tumor-promoting activity in thyroid cancer. Int. J. Cancer, 2010, 127(3), 521-531.
[http://dx.doi.org/10.1002/ijc.25068] [PMID: 19950223]
[20]
Rodprasert, W.; Virtanen, H.E.; Mäkelä, J.A.; Toppari, J. Hypogonadism and cryptorchidism. Front Endocrinol, 2020, 10, 906.
[http://dx.doi.org/10.3389/fendo.2019.00906]
[21]
Lottrup, G.; Nielsen, J.E.; Maroun, L.L.; Møller, L.M.A.; Yassin, M.; Leffers, H.; Skakkebæk, N.E.; Rajpert-De Meyts, E. Expression patterns of DLK1 and INSL3 identify stages of Leydig cell differentiation during normal development and in testicular pathologies, including testicular cancer and Klinefelter syndrome. Hum. Reprod., 2014, 29(8), 1637-1650.
[http://dx.doi.org/10.1093/humrep/deu124] [PMID: 24908673]
[22]
Steggink, L.C.; van Beek, A.P.; Boer, H.; Meijer, C.; Lubberts, S.; Oosting, S.F.; de Jong, I.J.; van Ginkel, R.J.; Lefrandt, J.D.; Gietema, J.A.; Nuver, J. Insulin-like factor 3, luteinizing hormone and testosterone in testicular cancer patients: Effects of β-hCG and cancer treatment. Andrology, 2019, 7(4), 441-448.
[http://dx.doi.org/10.1111/andr.12581] [PMID: 30609309]
[23]
Overvad, S.; Bay, K.; Bojesen, A.; Gravholt, C.H. Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis. Andrology, 2014, 2(3), 421-427.
[http://dx.doi.org/10.1111/j.2047-2927.2014.00204.x] [PMID: 24659579]
[24]
Freire, A.V.; Grinspon, R.P.; Rey, R.A. Importance of serum testicular protein hormone measurement in the assessment of disorders of sex development. Sex Dev., 2018, 12(1-3), 30-40.
[http://dx.doi.org/10.1159/000479572] [PMID: 28850950]
[25]
Chong, Y.H.; Pankhurst, M.W.; McLennan, I.S. The testicular hormones AMH, InhB, INSL3, and testosterone can be independently deficient in older men. J. Gerontol. A Biol. Sci. Med. Sci., 2017, 72(4), 548-553.
[PMID: 27470300]
[26]
Foresta, C.; Di Mambro, A.; Pagano, C.; Garolla, A.; Vettor, R.; Ferlin, A. Insulin-like factor 3 as a marker of testicular function in obese men. Clin. Endocrinol. (Oxf.), 2009, 71(5), 722-726.
[http://dx.doi.org/10.1111/j.1365-2265.2009.03549.x] [PMID: 19226271]
[27]
Ermetici, F.; Donadio, F.; Iorio, L.; Malavazos, A.E.; Dolci, A.; Peverelli, E.; Barbieri, A.M.; Morricone, L.; Chiodini, I.; Arosio, M.; Lania, A.; Beck-Peccoz, P.; Ambrosi, B.; Corbetta, S. Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: Effect of glycemic control and visceral adiposity on Leydig cell function. Eur. J. Endocrinol., 2009, 161(6), 853-859.
[http://dx.doi.org/10.1530/EJE-09-0203] [PMID: 19755411]
[28]
Anand-Ivell, R.; Ivell, R. Insulin-like factor 3 as a monitor of endocrine disruption. Reproduction, 2014, 147(4), R87-R95.
[http://dx.doi.org/10.1530/REP-13-0486] [PMID: 24256640]
[29]
Toft, G.; Jönsson, B.A.; Bonde, J.P.; Nørgaard-Pedersen, B.; Hougaard, D.M.; Cohen, A.; Lindh, C.H.; Ivell, R.; Anand-Ivell, R.; Lindhard, M.S. Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal Leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980–1996). Environ. Health Perspect., 2016, 124(1), 151-156.
[http://dx.doi.org/10.1289/ehp.1409288] [PMID: 26046833]
[30]
van Brakel, J.; de Muinck Keizer-Schrama, S.M.P.F.; Hazebroek, F.W.J.; Dohle, G.R.; de Jong, F.H. INSL3 and AMH in patients with previously congenital or acquired undescended testes. J. Pediatr. Surg., 2017, 52(8), 1327-1331.
[http://dx.doi.org/10.1016/j.jpedsurg.2017.03.064] [PMID: 28487028]
[31]
Santi, D.; Ivell, R.; Anand-Ivell, R.; De Toni, L.; Fanelli, F.; Mezzullo, M.; Pelusi, C.; Pagotto, U.; Belli, S.; Granata, A.R.M.; Roli, L.; Rochira, V.; Trenti, T.; Ferlin, A.; Simoni, M. Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome. Andrology, 2020. Online ahead of print
[http://dx.doi.org/10.1111/andr.12851] [PMID: 2593193]
[32]
Ferlin, A.; Perilli, L.; Gianesello, L.; Taglialavoro, G.; Foresta, C. Profiling Insulin Like Factor 3 (INSL3) signaling in human osteoblasts. PLoS One, 2011, 6(12), e29733.
[33]
Di Nisio, A.; De Toni, L.; Rocca, M.S.; Ghezzi, M.; Selice, R.; Taglialavoro, G.; Ferlin, A.; Foresta, C. Negative association between sclerostin and INSL3 in isolated human osteocytes and in klinefelter syndrome: New hints for testis-bone crosstalk. J. Clin. Endocrinol. Metab., 2018, 103(5), 2033-2041.
[http://dx.doi.org/10.1210/jc.2017-02762] [PMID: 29452406]
[34]
Baron, R.; Rawadi, G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology, 2007, 148(6), 2635-2643.
[http://dx.doi.org/10.1210/en.2007-0270] [PMID: 17395698]
[35]
Ferlin, A.; Pepe, A.; Gianesello, L.; Garolla, A.; Feng, S.; Giannini, S.; Zaccolo, M.; Facciolli, A.; Morello, R.; Agoulnik, A.I.; Foresta, C. Mutations in the insulin-like factor 3 receptor are associated with osteoporosis. J. Bone Miner. Res., 2008, 23(5), 683-693.
[http://dx.doi.org/10.1359/jbmr.080204] [PMID: 18433302]
[36]
Passeri, E.; Sansone, V.A.; Sconfienza, L.M.; Messina, C.; Meola, G.; Corbetta, S. Fragility fractures and bone mineral density in male patients affected by type 1 and type 2 myotonic dystrophy. Neuromuscul. Disord., 2020, 30(1), 28-34.
[http://dx.doi.org/10.1016/j.nmd.2019.11.006] [PMID: 31902642]
[37]
Coskun, G.; Sencar, L.; Tuli, A.; Saker, D.; Alparslan, M.M.; Polat, S. Effects of osteocalcin on synthesis of testosterone and INSL3 during adult leydig cell differentiation. Int. J. Endocrinol., 2019, 2019, 1041760.
[http://dx.doi.org/10.1155/2019/1041760] [PMID: 31558901]
[38]
Ferlin, A.; De Toni, L.; Agoulnik, A.I.; Lunardon, G.; Armani, A.; Bortolanza, S.; Blaauw, B.; Sandri, M.; Foresta, C. Protective role of testicular hormone INSL3 from atrophy and weakness in skeletal muscle. Front. Endocrinol. (Lausanne), 2018, 9, 562.
[http://dx.doi.org/10.3389/fendo.2018.00562] [PMID: 30323788]
[39]
Bhasin, S.; Brito, J.P.; Cunningham, G.R.; Hayes, F.J.; Hodis, H.N.; Matsumoto, A.M.; Snyder, P.J.; Swerdloff, R.S.; Wu, F.C.; Yialamas, M.A. Testosterone therapy in men with hypogonadism: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab., 2018, 103(5), 1715-1744.
[http://dx.doi.org/10.1210/jc.2018-00229] [PMID: 29562364]
[40]
Albrethsen, J.; Johannsen, T.H.; Jørgensen, N.; Frederiksen, H.; Sennels, H.P.; Jørgensen, H.L.; Fahrenkrug, J.; Petersen, J.H.; Linneberg, A.; Nordkap, L.; Bang, A.K.; Andersson, A.M.; Juul, A. Evaluation of serum insulin-like factor 3 quantification by LC-MS/MS as a biomarker of leydig cell function. J. Clin. Endocrinol. Metab., 2020, 105(6), dgaa145.
[http://dx.doi.org/10.1210/clinem/dgaa145] [PMID: 32211773]
[41]
Albrethsen, J.; Frederiksen, H.; Andersson, A.M.; Anand-Ivell, R.; Nordkap, L.; Bang, A.K.; Jørgensen, N.; Juul, A. Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum. Clin. Chem. Lab. Med., 2018, 56(11), 1913-1920.
[http://dx.doi.org/10.1515/cclm-2018-0171] [PMID: 29847312]

Rights & Permissions Print Cite
Article Metrics
24
1
1
© 2024 Bentham Science Publishers | Privacy Policy