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. 2023 Nov 1:14:1266730.
doi: 10.3389/fendo.2023.1266730. eCollection 2023.

Leydig cell metabolic disorder act as a new mechanism affecting for focal spermatogenesis in Klinefelter syndrome patients: a real world cross-sectional study base on the age

Huang Liu #  1 , Zhenhui Zhang #  2 , Yong Gao #  3 , Hai Lin  1 , Zhiyong Zhu  1 , Houbin Zheng  1 , Wenjing Ye  4 , Zefang Luo  1 , Zhaohui Qing  5 , Xiaolan Xiao  5 , Lei Hu  1 , Yu Zhou  1 , Xinzong Zhang  1
Affiliations

Leydig cell metabolic disorder act as a new mechanism affecting for focal spermatogenesis in Klinefelter syndrome patients: a real world cross-sectional study base on the age

Huang Liu et al. Front Endocrinol (Lausanne). .

Abstract

Background: Klinefelter's syndrome (KS) was once considered infertile due to congenital chromosomal abnormalities, but the presence of focal spermatozoa changed this. The key to predict and promote spermatogenesis is to find targets that regulate focal spermatogenesis.

Objective: To explore the trend of fertility changes in KS patients at different ages and identify potential therapeutic targets.

Methods: Bibliometric analysis was used to collect clinical research data on KS from the Web of Science Core Collection (WoSCC) from 1992 to 2022. A cross-sectional study was conducted on 75 KS patients who underwent microscopic testicular sperm extraction (mTESE) from 2017 to 2022 in the real world. The reproductive hormones, testicular histopathology, androgen receptors, insulin-like factor 3 (INSL3) receptors and sperm recovery rate (SRR) were analyzed.

Results: Male infertility, dysplasia, Sertoli cells, Leydig cells, testosterone and spermatogenesis were the research focuses related to KS. Luteinizing hormone (LH), testosterone, and INSL3 were evaluation indicators of Leydig cell function that fluctuate with age. Testosterone and LH peaked at ages 13-19 and 30-45, while INSL3 only peaked at ages 13-19. 27 patients (27/75) recovered sperm through mTESE and experienced SRR peaks at the ages of 20, 28, 34, and 37. The SRR of fibrosis patients was 46.15%, fatty degeneration was 7.14%, and melanosis was 40.00%. The INSL3 and androgen receptors were highly expressed and roughly balanced in focal spermatogenesis.

Conclusion: Abnormal metabolism of Leydig cells led to imbalanced expression of INSL3 and androgen receptors, which might be a potential target for spermatogenesis in KS.

Keywords: Klinefelter syndrome; Leydig cell; age; metabolic disorder; microscopic testicular sperm extraction; spermatogenic.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Process of bibliometric and visual analysis.
Figure 2
Figure 2
Overview of the real world research.
Figure 3
Figure 3
Publications and journals for quantitative analysis: (A) Publication output. (B) Literature types. (C) Average year publication of highly productive journals. (D) Average citation scores of highly productive journals.
Figure 4
Figure 4
Countries and authors for quantitative analysis: (A) The network map of countries. (B) Numbers of publications of countries (SCP, single country publication; MCP, multiple country publication. (C) Total citations of countries. (D–G) The top 15 authors in terms of number of publications, total citations, local citations and H-index. (H) Collaboration network.
Figure 5
Figure 5
Network and keywords for quantitative analysis: (A) Citation Network of documents. (B) Cocitation Network of references. (C) Network of keywords. (D) Network of KS. (E) Network of Leydig cells. (F) Chronological overlay of keywords. (G) Density of keywords.
Figure 6
Figure 6
Hormone indicators for quantitative analysis: (A) LH characteristics of literature. (B) T characteristics of the literature. (C) INSL3 characteristics of the literature. (D) Reproductive hormone characteristics of literature.
Figure 7
Figure 7
Distribution of KS patients: (A) Distribution of KS patients in China. (B) KS patients in Guangdong. (C) GDP of Guangdong cities in 2021.
Figure 8
Figure 8
Testicular classification of KS patients. (A) Atrophy (Atr). (B) Filamentous (Fil). (C) Hyaline (Hya). (D) Fat accumulation (Fta). (E) Vacuolation (Vac). (F) Melanoid transformation (Met). (G) Nodular (Nod). (H) Patchy (Pat). (I) Pectinicity (Pec).Green arrow: shaped and spermatogenic tubules.
Figure 9
Figure 9
Indicators between KS patients. (A) Johnson score. (B) Testicular tissue classification. (C) General classification of testicular tissue. (D) Patient count. (E) Johnson score of different ages. (F) Testicular volume at different ages. (G) Sperm outcome of different ages.
Figure 10
Figure 10
Indicators between KS patients of different ages: (A) E2. (B) FSH. (C) LH. (D) T. (E) Sperm outcome. (F) Comprehensive indicators. (G) FSH. (H) LH. (I) T. (J) E2. (K) Age. (L) Sperm outcome. (M) FSH. (N) LH. (O) T. (P) E2.
Figure 11
Figure 11
INSL3 receptor and androgen receptor in KS patients. (A) INSL3 between seminiferous tubules (green mark). (B) INSL3 in seminiferous tubules (green mark). (C) INSL3 in the seminiferous tubule of spermatozoa (green mark). (D) INSL3 in the seminiferous tubule without sperm (green mark). (E) INSL3 in the seminiferous tubule of spermatozoa (green mark, red fluorescence, 100×). (F) INSL3 in the seminiferous tubule of spermatozoa (green mark, red fluorescence, 200×). (G) INSL3 in the seminiferous tubule without sperm (green mark, red fluorescence, 100×). (H) INSL3 in the seminiferous tubule without sperm (green mark, red fluorescence, 200×). (I) Androgen receptor in the seminiferous tubule of spermatozoa (red mark, green fluorescence, 100×). (J) Androgen receptor in the seminiferous tubule of spermatozoa (red mark, green fluorescence, 200×). (K) Androgen receptor in the seminiferous tubule without sperm (red mark, green fluorescence, 100×). (L) Androgen receptor in the seminiferous tubule without sperm (red mark, green fluorescence, 200×). (M) The androgen receptor and INSL3 receptor in the seminiferous tubule of spermatozoa: ®: find the sperm seminiferous tubule. Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 100×. (N) The androgen receptor and INSL3 receptor in the seminiferous tubule of spermatozoa: Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 200×. (O) The androgen receptor and INSL3 receptor in the seminiferous tubule of spermatozoa: Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 500×. (P) The androgen receptor and INSL3 receptor in the seminiferous tubule of spermatozoa. INSL3 receptor: green fluorescence, marked in red circle. Androgen receptor: red fluorescence, marked in yellow circle. Overlapping androgen receptor and INSL3 receptor: marked in white box. 1000×. (Q) The androgen receptor and INSL3 receptor in the seminiferous tubule without sperm: ©: the seminiferous tubule without sperm. Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 100×. (R) The androgen receptor and INSL3 receptor in the seminiferous tubule without sperm: Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 200×. (S) The androgen receptor and INSL3 receptor in the seminiferous tubule without sperm: Green fluorescence: INSL3 receptor. Red fluorescence: androgen receptor. 500×. (T) The androgen receptor and INSL3 receptor in the seminiferous tubule without sperm: INSL3 receptor: green fluorescence, marked in red circle. 1000×.
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