Skip to main content

Advertisement

SpringerLink
Log in

Comparison of Clinical Characteristics and Spermatogenesis in CHH Patients Caused by PROKR2 and FGFR1 Mutations

  • Male Reproduction: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

A retrospective study was conducted to investigate the effect of gonadotropin or pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with PROKR2 (prokineticin receptor 2) or FGFR1 (fibroblast growth factor receptor 1) mutations. Clinical features, gonadotropin levels, testicular volume (TV), and sperm concentration in response to gonadotropin and pulsatile GnRH therapy were compared between groups with PROKR2 and FGFR1 mutations. Twelve patients with PROKR2 gene mutation and fourteen patients with FGFR1 gene mutation were included. The incidence of cryptorchidism in PROKR2 and FGFR1 groups was 16.7% and 50%, respectively (p = 0.110). The baseline TV in the PROKR2 group was larger than that in FGFR1 group (2.0 vs. 1.63, p = 0.047). The initial LH, FSH, and testosterone levels were similar between the two groups. Based on the analysis of achieving spermatogenesis using Kaplan-Meier and log-rank tests, the PROKR2 group demonstrated shorter period of seminal spermatozoa appearance than the FGFR1 group (χ2 = 8.297, p = 0.004); the median duration of achieving spermatogenesis in the PROKR2 and FGFR1 groups was 9 and 16 months, respectively. The PROKR2 mutation group exhibited shorter required time to achieve different sperm concentration thresholds (5, 10, and 15 million/mL) than the FGFR1 mutation group (p = 0.012, 0.024, and 0.040). In conclusion, the PROKR2 group achieved spermatogenesis easily than the FGFR1 group, possibly due to the lower prevalence of cryptorchidism and larger baseline testicular volume in the PROKR2 group.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Topaloglu AK, Kotan LD. Genetics of hypogonadotropic hypogonadism. Endocr Dev. 2016;29:36–49.

    Article  CAS  Google Scholar 

  2. Layman LC. Hypogonadotropic hypogonadism. Endocrinol Metab Clin N Am. 2007;36:283–96.

    Article  CAS  Google Scholar 

  3. Maione L, Dwyer AA, Francou B, Guiochonmantel A, Binart N, Bouligand J, et al. Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178:17-749.

  4. Amato L, Montenegro LR, Lerario AM, Jorge A, Guerra JG, Schnoll C, et al. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2019;181:103–19.

    Article  CAS  Google Scholar 

  5. Yu M. Study on the genetic diagnosis of congenital hypogonadotropic hypogonadism in male. In: Jiangsu University; 2018.

  6. Stamou MI, Georgopoulos NA. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism. 2018;86:124–34.

    Article  CAS  Google Scholar 

  7. Semple RK, Topaloglu AK. The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions. Clin Endocrinol. 2010;72:427–35.

    Article  CAS  Google Scholar 

  8. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci U S A. 2006;103:4140–5.

    Article  CAS  Google Scholar 

  9. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, et al. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. The Journal of Clinical Endocrinology & Metabolism. 2004;89:1079–88.

    Article  CAS  Google Scholar 

  10. Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Pinero A, Wolczynski S, et al. A comparative phenotypic study of Kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J Clin Endocrinol Metab. 2010;95:659–69.

    Article  CAS  Google Scholar 

  11. Jarzabek K, Wolczynski S, Lesniewicz R, Plessis G, Kottler ML. Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome. Adv Med Sci. 2012;57:314–21.

    Article  CAS  Google Scholar 

  12. Biesecker LG, Harrison SM. The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet Med. 2018;20:1687–8.

    Article  Google Scholar 

  13. Bhagavath B, Podolsky RH, Ozata M, Bolu E, Bick DP, Kulharya A, et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril. 2006;85:706–13.

    Article  CAS  Google Scholar 

  14. Topaloğlu AK. Update on the genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr E. 2018:113–22.

  15. Kim YJ, Osborn DP, Lee JY, Araki M, Araki K, Mohun T, et al. WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. EMBO Rep. 2018;19:269–89.

    Article  CAS  Google Scholar 

  16. Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, Carel JC, et al. Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. The Journal of Clinical Endocrinology & Metabolism. 2008;93:758–63.

    Article  CAS  Google Scholar 

  17. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab. 2009;94:801–8.

    Article  CAS  Google Scholar 

  18. Mao J. Influence of gene mutations on hypothalamus pituitary gonad axis function and gonadotropin induced spermatogenesis in male patients with idiopathic hypogonadotropic hypogonadism. In. Peking: Peking Union Medical College; 2012.

  19. Pitteloud N, Meysing A, Quinton R, Acierno JS, Dwyer AA, Plummer L, et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006;254-255:60–9.

    Article  CAS  Google Scholar 

  20. Sarfati J, Dode C, Young J. Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. Front Horm Res. 2010;39:121–32.

    Article  CAS  Google Scholar 

  21. Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2014;30:174–81.

    Article  CAS  Google Scholar 

  22. Rodprasert W, Virtanen HE, Makela JA, Toppari J. Hypogonadism and cryptorchidism. Front Endocrinol (Lausanne). 2019;10:906.

    Article  Google Scholar 

  23. Virtanen HE, Toppari J. Epidemiology and pathogenesis of cryptorchidism. Hum Reprod Update. 2008;14:49–58.

    Article  CAS  Google Scholar 

  24. Hadziselimovic NO, de Geyter C, Demougin P, Oakeley EJ, Hadziselimovic F. Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism. Urol Int. 2010;84:353–61.

    Article  CAS  Google Scholar 

  25. Cotton L, Gibbs GM, Sanchez-Partida LG, Morrison JR, de Kretser DM, O'Bryan MK. FGFR-1 [corrected] signaling is involved in spermiogenesis and sperm capacitation. J Cell Sci. 2006;119:75–84.

    Article  CAS  Google Scholar 

  26. Abreu AP, Trarbach EB, de Castro M, Frade Costa EM, Versiani B, Matias Baptista MT, et al. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008;93:4113–8.

    Article  CAS  Google Scholar 

  27. Li JD, Hu WP, Boehmer L, Cheng MY, Lee AG, Jilek A, et al. Attenuated circadian rhythms in mice lacking the prokineticin 2 gene. J Neurosci. 2006;26:11615–23.

    Article  CAS  Google Scholar 

  28. Negri L, Lattanzi R, Giannini E, De Felice M, Colucci A, Melchiorri P. Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats. Br J Pharmacol. 2004;142:181–91.

    Article  CAS  Google Scholar 

  29. Hu WP, Li JD, Zhang C, Boehmer L, Siegel JM, Zhou QY. Altered circadian and homeostatic sleep regulation in prokineticin 2-deficient mice. Sleep. 2007;30:247–56.

    PubMed  Google Scholar 

  30. Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? - a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol. 2017;86:75–87.

    Article  CAS  Google Scholar 

  31. Prior M, Stewart J, McEleny K, Dwyer AA, Quinton R. Fertility induction in hypogonadotropic hypogonadal men. Clin Endocrinol. 2018;89:712–8.

    Article  CAS  Google Scholar 

  32. Ortac M, Hidir M, Salabas E, Boyuk A, Bese C, Pazir Y, et al. Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism. Asian J Androl. 2019;21:623–7.

    Article  CAS  Google Scholar 

  33. Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med. 1985;313:651–5.

    Article  CAS  Google Scholar 

  34. Kirk JM, Savage MO, Grant DB, Bouloux PM, Besser GM. Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism. Clin Endocrinol. 1994;41:57–63.

    Article  CAS  Google Scholar 

  35. Liu Z, Mao J, Xu H, Wang X, Huang B, Zheng J, et al. Gonadotropin-induced spermatogenesis in CHH patients with cryptorchidism. Int J Endocrinol. 2019;2019:6743489.

    PubMed  PubMed Central  Google Scholar 

  36. Ivell R, Hartung S. The molecular basis of cryptorchidism. Mol Hum Reprod. 2003;9:175–81.

    Article  CAS  Google Scholar 

  37. Imamoglu M, Bulbul SS, Kaklikkaya N, Sarihan H. Oxidative, inflammatory and immunologic status in children with undescended testes. Pediatr Int. 2012;54:816–9.

    Article  CAS  Google Scholar 

  38. Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab. 2011;22:249–58.

    CAS  PubMed  Google Scholar 

  39. Martin C, Balasubramanian R, Dwyer AA, Au MG, Sidis Y, Kaiser UB, et al. The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev. 2011;32:225–46.

    Article  CAS  Google Scholar 

  40. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab. 2008;93:3551–9.

    Article  CAS  Google Scholar 

  41. Dodé C, Rondard P. PROK2/PROKR2 signaling and Kallmann syndrome. Front Endocrinol (Lausanne). 2013;4:19.

    Article  Google Scholar 

Download references

Funding

This work was supported by the National Key Research and Development Program of China (2016YFC0905102, 2016YFA0101003); CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-002, 2017-I2M-3-007); the Project of National Natural Science Foundation of China (81771576); and Beijing Municipal Natural Science Foundation (7202151, 7212080).

Author information

Author notes

  1. Shuying Li and Yaling Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China

    Shuying Li, Yaling Zhao, Min Nie, Yufan Yang, Ming Hao, Jiangfeng Mao & Xueyan Wu

Authors
  1. Shuying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yaling Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yufan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiangfeng Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueyan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jiangfeng Mao or Xueyan Wu.

Ethics declarations

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The protocol was approved by the ethics committee of Peking Union Medical College Hospital (JS-1111).

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Zhao, Y., Nie, M. et al. Comparison of Clinical Characteristics and Spermatogenesis in CHH Patients Caused by PROKR2 and FGFR1 Mutations. Reprod. Sci. 28, 3219–3227 (2021). https://doi.org/10.1007/s43032-021-00609-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00609-z

Keywords

Search

Navigation