Leydig cell micronodules are a common finding in testicular biopsies from men with impaired spermatogenesis and are associated with decreased testosterone/LH ratio

Abstract

To assess the biological significance of Leydig cell 'hyperplasia' in man, Leydig cell distribution, volume, and function were studied in patients with infertility or testicular cancer and in suddenly deceased controls. A total of 156 biopsies from 95 patients and 18 necropsies from 13 controls were examined using a semi-quantitative stereological method. In patients, serum concentrations of testosterone, sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and inhibin-B were correlated with the findings on histological examination. Leydig cell clusters of more than 15 cells in a cross-section, for which we proposed the name 'micronodules', were frequently seen in testicles exhibiting Sertoli-cell-only syndrome (SCO), a mixed pattern of impaired spermatogenesis, or complete spermatogenesis in combination with elevated FSH. Median numbers of micronodules per 1.77 mm(2) (four fields of vision) in these three histological patterns were 6, 4, and 3.5, respectively. In contrast, micronodules were only occasionally observed in testicular biopsies from patients with complete spermatogenesis and normal gonadotrophin levels (median 1), and were rare in testes from controls (median = 0, p = 0.02). The proportion of testicular tissue occupied by Leydig cells increased with decreasing spermatogenic capacity. In contrast, the total volume of Leydig cells per testis was roughly comparable irrespective of the histological pattern, with the exception of testes with bilateral micronodules, which had significantly increased Leydig cell volume compared to those without micronodules. The number of micronodules correlated positively to LH (r = 0.577, p < 0.01) and FSH (r = 0.595, p < 0.01) and the presence of micronodules was most pronounced in the hyperstimulated testes, as reflected by an increased LH/testosterone ratio. In conclusion, Leydig cell micronodules were more frequent in biopsies with impaired spermatogenesis and associated with decreased ratios of testicular hormones to gonadotrophins. The presence of micronodules thus seems to be a histological marker of testicular failure in man.

Phthalate-induced pathology in the foetal testis involves more than decreased testosterone production

“…In fact, testicular biopsies from infertile men with impaired spermatogenesis showed Leydig cell clusters which have the appearance of Leydig cell hyperplasia. These men have decreased testosterone:LH ratio (Holm et al 2003) and testosterone:oestradiol ratio (Andersson et al 2004). This indicates a role of oestrogen in testes with poor spermatogenesis, although the mechanism is not understood.…”

Leydig cell clustering and Reinke crystal distribution in relation to hormonal function in adult patients with testicular dysgenesis syndrome (TDS) including cryptorchidism

“…Surprisingly, the distribution of RCs did not correlate with the severity of androgenic dysfunction in TDS patients with LC micronodules, which was reflected in this study by lower serum testosterone/LH-ratios, decreased serum inhibin B and by reduced testis size, in line with our previous study. 5 In another study, we have demonstrated that LC micronodules in patients with TDS and Klinefelter syndrome, a condition known for very large clusters of LCs, contain proportionally higher numbers of immature LCs due to an increased renewal of the LCs stimulated by LH. 6 The data in the present study provides evidence that the scarcity of RCs may be a characteristic feature of immature adult LCs, this hypothesis being in concert with previous studies of hyperplastic LCs in infertile patients and men with Klinefelter syndrome.…”

“…4 The LC micronodules, defined as more than 15 LCs in a cross-section, have previously been associated with a low testosterone/luteinising hormone (LH)-ratio, reflecting an endocrine hypofunction. 4,5 It was recently found that micronodules contain cells at different stages of differentiation with significantly increased proportions of immature LCs within micronodules in patients with germ cell tumours and in patients with Klinefelter syndrome, confirming the importance of stimulation by LH or human chorionic gonadotropin (hCG). 6 Whether the aggregation of LCs is a feature linked to impaired testis development or only represents a post-pubertal compensation for lower androgen levels has not been firmly established.…”

Serum levels of perfluorinated compounds and sperm Y:X chromosome ratio in two European populations and in Inuit from Greenland

“…However, these rats also suffered a significant body weight loss and subsequently also smaller testis weights, which may explain the hampered testosterone secretion. Lowered testosterone levels and Leydig cell hyperplasia are common features among infertile men [58,59] and higher levels of PFOA and PFOS has previously been shown in infertile men [60]. On the other hand, there are also studies showing no adverse PFOA or PFOS-effects on semen parameters in neither men [41] nor rats [42].…”