Abstract
OBJECTIVE
Testicular dysgenesis syndrome (TDS) comprises testicular germ cell cancer, cryptorchidism and some cases of male infertility and hypospadias, which can be linked to impairment of intrauterine gonadal development. Among histological signs of TDS, large Leydig cell (LC) clusters (micronodules) are frequently present. This study aimed to investigate possible associations of LC micronodules with the presence of Reinke crystals and hormonal function of LCs, the latter primarily reflected by serum concentrations of luteinising hormone (LH) and testosterone, in patients with TDS.
DESIGN
A retrospective study of 101 andrological patients with TDS (infertility with and without a history of cryptorchidism or presence of germ cell neoplasia in situ) and 20 controls with normal testis histology and LC-function. Archived testicular biopsies were re-evaluated for the presence of LC micronodules and Reinke crystals and the findings were correlated with testis size and serum concentrations of LH, follicle-stimulating hormone (FSH), testosterone, inhibin B, estradiol and sex hormone binding globulin (SHBG).
RESULTS
TDS patients with bilateral LC micronodules had significantly lower concentrations of LH, FSH and inhibin B, a lower testosterone/LH-ratio and smaller testis sizes compared to TDS-patients lacking this feature. Presence of LC micronodules was correlated with a lower number of Reinke crystals, while cryptorchid testes had a significantly higher number of crystals than normally descended TDS testes.
CONCLUSION
LC micronodules appear to be a compensatory mechanism caused by androgenic failure and are presumably driven by high concentrations of LH. A relative paucity of Reinke crystals in LCs within micronodules in normally descended TDS testes may be a feature of recently renewed immature Leydig cells. The increased number of Reinke crystals in LCs in testes that were either undescended at birth or are persistently undescended could indicate an impairment of LC renewal in cryptorchidism.
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Skakkebaek NE, Rajpert-De Meyts E, Main KM, 2001 Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16: 972–978.
Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, et al, 2016 Male reproductive disorders and fertility trends: Influences of Environment and Genetic Susceptibility. Physiol Rev 96: 55–97.
Jørgensen N, Rajpert-De Meyts E, Main KM, Skakkebaek NE, 2010 Testicular dysgenesis syndrome comprises some but not all cases of hypospadias and impaired spermatogenesis. Int J Androl 33: 298–303.
Joensen UN, Jørgensen N, Rajpert-De Meyts E, Skakkebaek NE, 2008 Testicular dysgenesis syndrome and Leydig cell function. Basic Clin Pharmacol Toxicol 102: 155–161.
Holm M, Rajpert-De Meyts E, Andersson AM, Skakkebaek NE, 2003 Leydig cell micronodules are a common finding in testicular biopsies from men with impaired spermatogenesis and are associated with decreased testosterone/LH ratio. J Pathol 199: 378–386.
Lottrup G, Nielsen JE, Maroun LL et al, 2014 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 29: 1637–1650.
Prince FP, 2001 The triphasic nature of Leydig cell development in humans, and comments on nomenclature. J Endocrinol 168: 213–216.
Zimmermann S, Steding G, Emmen JM, et al, 1999 Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13: 681–691.
Bay K, Main KM, Toppari J, Skakkebaek NE, 2011 Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nat Rev Urol 8: 187–196.
Landreh L, Spinnler K, Schubert K, et al, 2014 Human testicular peritubular cells host putative stem Leydig cells with steroidogenic capacity. J Clin Endocrinol Metab 99: E1227–1235.
Reinke F, 1896 Beiträge zur histologie des Menschen. I. Krystalloidbildung in den interstitiellen Zellen des menschlichen Hodens. Arch Mikrosk Anat 47: 34–44.
Mori H, Fukunishi R, Fujii M, Hataji K, Shiraishi T, Matsumoto K, 1978 Stereological analysis of Reinke’s crystals in human Leydig cells. Virchows Arch A. Pathol Anat Histol 380: 1–9.
Paniagua R, Amat P, Nistal M, Martin A, 1986 Ultra-structure of Leydig cells in human ageing testes. J Anat 146: 173–183.
Nagano T, Otsuki I, 1971 Reinvestigation of the fine structure of Reinke’s crystal in the human testicular interstitial cell. J Cell Biol 51: 148–161.
Kozina V, Geist D, Kubinová L, et al, 2011 Visualization of Reinke’s crystals in normal and cryptorchid testis. Histochem Cell Biol 135: 215–228.
Mesa H, Gilles S, Smith S, Dachel S, Larson W, Manivel JC, 2015 The mystery of the vanishing Reinke crystals. Hum Pathol 46: 600–606.
Sasagawa I, Nakada T, Kubota Y et al, 1995 Ultrastructure of Leydig cells in Down’s syndrome. Int Urol and Nephrol 27: 585–591.
Aumüller G, Peter S, 1986 Immunohistochemical and ultrastructural study of Sertoli cells in androgen insensitivity. Int J Androl 9: 99–108.
Longo FJ, Coleman SA, Givens JR, 1975 Ultrastructural analysis of the testes in male pseudohermaphrodism reductase. Am J C Pathol 64: 145–154.
Al-Agha OM, Axiotis CA, 2007 An in-depth look at Leydig cell tumor of the testis. Arch Pathol Lab Med 131: 311–317.
Kim I, Young RH, Scully RE, 1985 Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 9: 177–192.
Feldman PS, Kovacs K, Horvath E, Adelson GL, 1982 Malignant Leydig cell tumor: clinical, histologic and electron microscopic features. Cancer 49: 714–721.
Lenz S, Thomsen JK, Giwercman A, Hertel NT, Hertz J, Skakkebaek NE, 1994 Ultrasonic texture and volume of testicles in infertile men. Hum Reprod 9: 878–881.
Skakkebaek NE, 1972 Possible carcinoma-in-situ of the testis. Lancet 2: 516–517.
Ulbright TM, Amin MB, Balzer B et al, 2016 Germ cell tumours. In: Moch H, Humphrey PA, Reuter VE, Ulbright TM (Eds). WHO classification of tumours of the urinary system and male genital organs, 4th Edition. IARC Press, pp, 189–226.
Hoei-Hansen CE, Holm M, Rajpert-De Meyts E, Skakkebæk NE, 2003 Histological evidence of testicular dysgenesis in contralateral biopsies of 218 patients with testicular germ cell cancer. J Pathol 200: 370–374.
McLachlan R, Rajpert-De Meyts E, Hoei-Hansen C, De Kretser DM, Skakkebaek NE, 2007 Histological evaluation of the human testis: approaches to optimizing the clinical value of assessment: Mini review. Hum Reprod 22: 2–16.
Söderström KO, 1986 Leydig cell hyperplasia. Arch Androl 17: 57–65.
Naughton CK, Nadler RB, Basler JW, Humphrey PA, 1998 Leydig cell hyperplasia. Br J Urol 81: 282–289.
Ježek D, Geist D, Banek LJ et al, 2007 Reinke’s Crystals in Infertile Patients. Acta Clin Croat 46: 220.
Paniagua R, Nistal M, Bravo MP, 1984 Leydig cell types in primary testicular disorders. Hum Pathol 15: 181–190.
Ivell R, Wade JD, Anand-Ivell R, 2013 INSL3 as a biomarker of Leydig cell functionality. Biol Reprod 88: 147.
Justrabo E, Cabanne F, Michiels R, et al, 1978 A complete form of testicular feminisation syndrome; a light and electron microscopy study. J Pathol 126: 165–171.
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Soerensen, R.R., Johannsen, T.H., Skakkebaek, N.E. et al. Leydig cell clustering and Reinke crystal distribution in relation to hormonal function in adult patients with testicular dysgenesis syndrome (TDS) including cryptorchidism. Hormones 15, 518–526 (2016). https://doi.org/10.14310/horm.2002.1708
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DOI: https://doi.org/10.14310/horm.2002.1708