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

Lottrup, Grete; Nielsen, John; Maroun, Lisa Leth; Møller, Lars Alling; Yassin, Musaab; Leffers, Henrik; Skakkebæk, Niels E.; Meyts, Ewa Rajpert‐De

doi:10.1093/humrep/deu124

Cited by 61 publications

(66 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. [28][29][30][31] In this study we re-investigated a previously reported finding that the number of RCs in undescended testes may be significantly greater than in normally descended testes.…”

Section: Discussionsupporting

confidence: 88%

“…In a previous study, the heterogeneity of LCs arranged in micronodules was confirmed by the distinct immunohistochemical markers for different stages of differentiation. 6 A marker of immature endocrine cells, DLK1, was predominantly found in progenitor cells, whereas INSL3, a well-known marker of LC maturity, was abundant in mature polygonal LCs. 32 The presence of DLK1 was positively correlated to the total number of LCs and up-regulated in the TDS patients, a phenomenon consistent with immaturity of LCs arranged in clusters.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…delta-like 1 homolog (DLK1) and INSL3] and steroidogenic function. 6,10 Among morphological hallmarks of LCs in the adult testis are the polygonal cell shape and the presence of Reinke crystals (RCs) shown in Figure 1, which are usually located within the cytoplasm or-very infrequently-in the nucleus of some LCs. RCs are not found in LCs progenitors and allegedly increase in number with increasing age.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Soerensen¹,

Johannsen²,

Skakkebæk³

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Soerensen¹,

Johannsen²,

Skakkebæk³

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Tissue sections from adult orchiectomy specimens containing GCNIS and normal testis parenchyma, and biopsies with TART were used as positive controls. A standard three-layered indirect immunoperoxidase protocol was applied, using Histostain Kit (Zymed, San Francisco, CA, USA) followed by colour development with aminoethyl-carbazole substrate (DAKO, Glostrup, Denmark), as described previously (18). To control for specificity of each antibody, a serial section was stained with the full protocol but with the primary antibody replaced by dilution buffer.…”

Section: Histology and Ihcmentioning

confidence: 99%

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Burckhardt

Udhane

Marti

et al. 2015

European Journal of Endocrinology

View full text Add to dashboard Cite

Context: 3b-hydroxysteroid dehydrogenase deficiency (3bHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3bHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk. Objective: To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation. Methods: Biochemical, genetic and immunohistochemical investigations on human biomaterials. Results: A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes. Conclusions: The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.

show abstract

Germ cell loss in Klinefelter syndrome: When and why?

Willems

Gies

Saen

2020

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Klinefelter syndrome (KS) is a quite common disorder with an incidence of 1-2 in 1000 newborn males. Most patients are diagnosed in the light of a clinical check-up when consulting a fertility clinic with an unfulfilled child wish. Infertility in KS patients is caused by a massive germ cell loss, leading to azoospermia in more than 90% of the adult patients. Most seminiferous tubules in the adult KS testis are degenerated or hyalinized and testicular fibrosis can be observed, starting from puberty. However, focal spermatogenesis can be found in the testis of some patients. This offers the opportunity to extract spermatozoa from the testis by testicular sperm extraction. However, TESE is only successful in about half of the KS adults seeking to father children. The reason for the germ cell loss remains unclear. To date, it is still debated whether the testicular tissue changes and the germ cell loss seen in KS is directly caused by an altered X-linked gene expression, the altered somatic environment or a deficiency in the germ cells. In this review, we provide an overview of the current knowledge about the germ cell loss in KS patients.

show abstract

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

Abstract: This work was funded by Rigshospitalet's research funds, the Danish Cancer Society and Kirsten and Freddy Johansen's foundation. The authors have no conflicts of interest.

Cited by 61 publications

References 42 publications

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

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

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Germ cell loss in Klinefelter syndrome: When and why?

Contact Info

Product

Resources

About