Deregulation of Sertoli and Leydig cells function in patients with Klinefelter syndrome as evidenced by testis transcriptome analysis

Insulin-like factor 3 (INSL3) serum levels were measured in 135 andrologically well-characterized normal men and 85 patients with testicular disorders to investigate how the hormone, which is a major secretory product of human Leydig cells, is related to testosterone (T), LH, and semen quality. INSL3 was measured by using a newly developed fluorescence immunoassay. Median (2.5–97.5 percentiles) INSL3 serum levels were as follows: normal men (n = 135), 0.99 (0.55–1.73) ng/ml; infertile men (n = 23), 1.11 (0.60–2.07) ng/ml; anorchid men (n = 21), nondetectable (ND); patients with 47, XXY, Klinefelter syndrome (n = 21), 0.12 (ND–0.78) ng/ml; men with hypogonadotropic hypogonadism and T substitution (n = 11), ND; and men with hypogonadotropic hypogonadism and human chorionic gonadotropin (hCG) treatment (n = 5), 0.36 (0.13–0.73) ng/ml. Before testicular biopsy, two infertile men had blood samples drawn directly from vena spermatica. Here, the serum INSL3 levels were 15-fold higher than in serum from peripheral blood samples (13.84 and 14.00 ng/ml, respectively). In two unilaterally orchiectomized former testis cancer patients, who underwent hCG stimulation test, INSL3 serum levels were unchanged 72 and 96 h after hCG stimulation. In conclusion, we provide a normal range for INSL3 serum levels in adult men and show that the majority, if not all, circulating INSL3 derives from the testes. Furthermore, our data strongly indicate that INSL3 secretion is dependent on the differentiating effect of LH on Leydig cells but independent of the steroidogenic LH-mediated action. Thus, even though T and INSL3 are both dependent on LH, these two Leydig cell hormones are regulated differently.

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Faculty Opinions recommendation of Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733284251.793555186 ◽

2019 ◽

Author(s):

Robert Oates

Keyword(s):

Transcriptome Analysis ◽

Leydig Cells ◽

Adult Human

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A SIMPLE CLINICAL TEST FOR MEASURING THE SERUM TESTOSTERONE RESPONSE TO INTRAVENOUS INFUSION OF HUMAN CHORIONIC GONADOTROPHIN (HCG)

Acta Endocrinologica ◽

10.1530/acta.0.0730790 ◽

1973 ◽

Vol 73 (4) ◽

pp. 790-793 ◽

Cited By ~ 5

Author(s):

F. Vivanco ◽

P. Gonzalez-Gancedo ◽

F. Ramos

Keyword(s):

Leydig Cells ◽

Klinefelter Syndrome ◽

Serum Testosterone ◽

Human Chorionic Gonadotrophin ◽

Clinical Test ◽

Maximal Increase ◽

Testosterone Secretion ◽

Competitive Protein Binding ◽

Normal Women ◽

Normal Men

ABSTRACT A simple clinical test for measuring the blood testosterone response to intravenous infusions of HCG is described. Testosterone was measured in serum by a competitive protein-binding method at 0, 4, 12 and 24 h after the iv infusion of 5000 IU of HCG. Normal men showed a maximal increase of serum testosterone of about 2.5 times the basal levels at 12–24 h after starting the HCG infusion. Normal women did not respond at all to HCG stimulation. Four cases of proven Klinefelter syndrome (XXY) had basal testosterone values higher than in women but significantly lower than in normal men and did not show any response to HCG stimulation. In two orchidectomized patients with very low basal levels of serum testosterone the response to iv HCG was also negative. The test appears to measure specifically the testosterone secretion of the Leydig cells and may be very useful for the differential diagnosis of male hypogonadal syndromes.

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Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells

Cell Death and Disease ◽

10.1038/s41419-018-0671-1 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 7

Author(s):

Sofia Boeg Winge ◽

Marlene Danner Dalgaard ◽

Kirstine G Belling ◽

Jacob Malte Jensen ◽

John Erik Nielsen ◽

...

Keyword(s):

Transcriptome Analysis ◽

Leydig Cells ◽

Adult Human

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2037 AGE DEPENDENT DEGENERATION OF SERTOLI AND LEYDIG CELLS IN ADOLESCENTS AND MEN WITH KLINEFELTER SYNDROME: A HISTOLOGICAL ANALYSIS

The Journal of Urology ◽

10.1016/j.juro.2013.02.2456 ◽

2013 ◽

Vol 189 (4S) ◽

Author(s):

Michael Funaro ◽

Akanksha Mehta ◽

Russell Simons ◽

Alexander Bolyakov ◽

Anna Mielnik ◽

...

Keyword(s):

Leydig Cells ◽

Histological Analysis ◽

Klinefelter Syndrome ◽

Age Dependent

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Male 41, XXY* Mice as a Model for Klinefelter Syndrome: Hyperactivation of Leydig Cells

Endocrinology ◽

10.1210/en.2009-1396 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2898-2910 ◽

Cited By ~ 38

Author(s):

Joachim Wistuba ◽

C. Marc Luetjens ◽

Jan-Bernd Stukenborg ◽

Andreas Poplinski ◽

Steffi Werler ◽

...

Keyword(s):

Germ Cell ◽

X Chromosome ◽

Leydig Cell ◽

Leydig Cells ◽

Cell Function ◽

Klinefelter Syndrome ◽

Cell Loss ◽

Endocrine Function ◽

Maximal Response ◽

Different Ages

Sex chromosome imbalance in males is linked to a supernumerary X chromosome, a condition resulting in Klinefelter syndrome (KS; 47, XXY). KS patients suffer from infertility, hypergonadotropic hypogonadism, and cognitive impairments. Mechanisms of KS pathophysiology are poorly understood and require further exploration using animal models. Therefore, we phenotypically characterized 41, XXY* mice of different ages, evaluated observed germ cell loss, studied X-inactivation, and focused on the previously postulated impaired Leydig cell maturation and function as a possible cause of the underandrogenization seen in KS. Xist methylation analysis revealed normal X-chromosome inactivation similar to that seen in females. Germ cell loss was found to be complete and to occur during the peripubertal phase. Significantly elevated FSH and LH levels were persistent in 41, XXY* mice of different ages. Although Leydig cell hyperplasia was prominent, isolated XXY* Leydig cells showed a mature mRNA expression profile and a significantly higher transcriptional activity compared with controls. Stimulation of XXY* Leydig cells in vitro by human chorionic gonadotropin indicated a mature LH receptor whose maximal response exceeded that of control Leydig cells. The hyperactivity of Leydig cells seen in XXY* mice suggests that the changes in the endocrine milieu observed in KS is not due to impaired Leydig cell function. We suggest that the embedding of Leydig cells into the changed testicular environment in 41 XXY* males as such influences their endocrine function.

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