Biochemical Analysis of Congenital Hypogonadotropic Hypogonadism in the Context of Male Infertility: A Comprehensive Review
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Abstract
Background: Male infertility encompasses various etiologies, with Congenital Hypogonadotropic Hypogonadism (CHH) standing out as a significant factor. CHH arises from multiple systems, including genetic abnormalities and hormonal imbalances that impair reproductive capabilities.
Objective: This review aims to dissect the biochemical underpinnings of CHH and evaluate its impact on male infertility, highlighting the complexities in its diagnosis and therapeutic management.
Methods: The analysis involved a review of current literature on the genetic causes and hormonal disruptions associated with CHH. Diagnostic criteria were assessed based on biochemical markers and clinical symptoms. Treatment efficacy was evaluated through outcomes of hormone replacement therapy, surgical interventions, and assisted reproductive technologies.
Results: The majority of CHH patients treated with hormone replacement therapy demonstrated improved sexual maturation and fertility, with approximately 70% achieving spermatogenesis. Surgical interventions corrected anatomical defects in 90% of cases, while assisted reproductive technologies resulted in successful pregnancies in 60% of treated individuals.
Conclusion: CHH significantly affects male reproductive health, influencing testicular development and endocrine function. Advances in diagnostic and treatment strategies have enhanced management outcomes, but ongoing research is essential for developing more targeted therapies.
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References
Abbara, A., Koysombat, K., Phylactou, M., Eng, P. C., Clarke, S., Comninos, A. N., Yang, L., Izzi-Engbeaya, C., Hanassab, S., Smith, N., Jayasena, C. N., Xu, C., Quinton, R., Pitteloud, N., Binder, G., Anand-Ivell, R., Ivell, R., & Dhillo, W. S. (2022). Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men. Frontiers in Endocrinology, 13(November), 1–11. https://doi.org/10.3389/fendo.2022.1076984
Acierno, J. S., Xu, C., Papadakis, G. E., Niederländer, N. J., Rademaker, J. D., Meylan, J., Messina, A., Kolesinska, Z., Quinton, R., Lang-Muritano, M., Bartholdi, D., Halperin, I., De Geyter, C., Bouligand, J., Bartoloni, L., Young, J., Santoni, F. A., & Pitteloud, N. (2020). Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism. Genetics in Medicine, 22(11), 1759–1767. https://doi.org/10.1038/s41436-020-0896-0
Al Sayed, Y., & Howard, S. R. (2023). Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective. European Journal of Human Genetics, 31(4), 387–394. https://doi.org/10.1038/s41431-022-01261-
Amato, Lorena Guimaraes Lima, Luciana Ribeiro Montenegro, Antonio Marcondes Lerario, Alexander Augusto Lima Jorge, Gil Guerra Junior, Caroline Schnoll, Alessandra Covallero Renck et al. "New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism." European journal of endocrinology 181, no. 2 (2019): 103-119.
Arpitha, K. J. (2020). Transvaginal Ultrasound Diagnosis of Polycystic Ovarian Syndrome and its Correlation with Biochemical Parameters (Doctoral dissertation, Rajiv Gandhi University of Health Sciences (India).
Article, O. (2020). Clinical Pediatric. 31(1), 1–6. https://doi.org/10.1297/cpe.31.2021-0070
Barratt, C. L., Björndahl, L., De Jonge, C. J., Lamb, D. J., Osorio Martini, F., McLachlan, R., ... & Tournaye, H. (2017). The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance—challenges and future research Bollino, A., Cangiano, B., Goggi, G., Federici, S., Duminuco, P., Giovanelli, L., ... & Bonomi, M. (2020). Pubertal delay. The challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP): a narrative review. Minerva Pediatrica, 72(4), 278-287.opportunities. Human reproduction update, 23(6), 660-680.
Butz, H., Nyírő, G., Kurucz, P. A., Likó, I., & Patócs, A. (2021). Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice. Human Genetics, 140(1), 113–134. https://doi.org/10.1007/s00439-020-02148-0
Cangiano, B., Swee, D. S., Quinton, R., & Bonomi, M. (2021). Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. In Human Genetics (Vol. 140, Issue 1). Springer Berlin Heidelberg. https://doi.org/10.1007/s00439-020-02147-1
Cangiano, B., Swee, D. S., Quinton, R., & Bonomi, M. (2021). Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Human Genetics, 140(1), 77-111.
Cannarella, R., Gusmano, C., Condorelli, R. A., Bernini, A., Kaftalli, J., Maltese, P. E., Paolacci, S., Dautaj, A., Marceddu, G., Bertelli, M., La Vignera, S., & Calogero, A. E. (2023). Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series. International Journal of Molecular Sciences, 24(8), 1–17. https://doi.org/10.3390/ijms24087428
Dutta, S., Sengupta, P., & Muhamad, S. (2019). Male reproductive hormones and semen quality. Asian Pacific Journal of Reproduction, 8(5).
Festa, A., Umano, G. R., Miraglia del Giudice, E., & Grandone, A. (2020). Genetic Evaluation of Patients With Delayed Puberty and Congenital Hypogonadotropic Hypogonadism: Is it Worthy of Consideration? Frontiers in Endocrinology, 11(May), 1–11. https://doi.org/10.3389/fendo.2020.00253
Foran, D., Chen, R., Jayasena, C. N., Minhas, S., & Tharakan, T. (2023). The use of hormone stimulation in male infertility. Current Opinion in Pharmacology, 68, 102333. https://doi.org/10.1016/j.coph.2022.102333
Fraietta, R., Zylberstejn, D. S., & Esteves, S. C. (2013). Hypogonadotropic hypogonadism revisited. Clinics, 68(SUPPL. 1), 81–88. https://doi.org/10.6061/clinics/2013(Sup01)09
Gach, A., Pinkier, I., Sałacińska, K., Szarras-Czapnik, M., Salachna, D., Kucińska, A., & Sakowicz, A. (2020). Identification of gene variants in a cohort of hypogonadotropic hypogonadism: diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease. Molecular and Cellular Endocrinology, 517, 110968.
Gach, A., Pinkier, I., Wysocka, U., Sałacińska, K., Salachna, D., Szarras-Czapnik, M., Pietrzyk, A., Sakowicz, A., Nykel, A., Rutkowska, L., Rybak-Krzyszkowska, M., Socha, M., Jamsheer, A., & Jakubowski, L. (2022). New findings in oligogenic inheritance of congenital hypogonadotropic hypogonadism. Archives of Medical Science, 18(2), 353–364. https://doi.org/10.5114/aoms.2020.98909
Kathrins, M., & Niederberger, C. (2016). Diagnosis and treatment of infertility-related male hormonal dysfunction. Nature Reviews Urology, 13(6), 309-323.
Kokoreva, K. D., Chugunov, I. S., & Bezlepkina, O. B. (2021). Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism. Problemy Endokrinologii, 67(4), 46–56. https://doi.org/10.14341/probl12787
Lee, H. S., Shim, Y. S., & Hwang, J. S. (2022). Treatment of congenital hypogonadotropic hypo-gonadism in male patients. Annals of Pediatric Endocrinology and Metabolism, 27(3), 176–182. https://doi.org/10.6065/apem.2244208.104
Li, X., Guo, Y., Wang, X., Li, H., Mao, J., Yan, S., Luo, G., Wang, R., Wu, X., & Li, Y. (2023). Seminal plasma metabolomics signatures of normosmic congenital hypogonadotropic hypogonadism. Heliyon, 9(4), e14779. https://doi.org/10.1016/j.heliyon.2023.e14779
Liang, Y., Yang, X., Li, Y., Lei, L., Lan, Y., & Wang, S. (2023). Successful pregnancy and delivery after ovulation induction therapy in a woman with congenital hypogonadotropic hypogonadism: a case report. BMC Pregnancy and Childbirth, 23(1), 1–6. https://doi.org/10.1186/s12884-023-05682-7
Louden, E. D., Poch, A., Kim, H. G., Ben-Mahmoud, A., Kim, S. H., & Layman, L. C. (2021). Genetics of hypogonadotropic Hypogonadism—Human and mouse genes, inheritance, oligogenicity, and genetic counseling. Molecular and Cellular Endocrinology, 534, 111334. https://doi.org/10.1016/j.mce.2021.111334
Maione, L., Sarfati, J., Gonfroy-Leymarie, Cc. D. sign©lin., Salenave, S., Brailly-Tabard, S., Chanson, P., Trabado, Sc. D. sign©verin., Kaiser, U. B., & Young, J. (2022). Reproductive Phenotypes in Men With Acquired or Congenital Hypogonadotropic Hypogonadism: A Comparative Study. Journal of Clinical Endocrinology and Metabolism, 107(7), E2812–E2824. https://doi.org/10.1210/clinem/dgac194
Messina, A., Pulli, K., Santini, S., Acierno, J., Känsäkoski, J., Cassatella, D., Xu, C., Casoni, F., Malone, S. A., Ternier, G., Conte, D., Sidis, Y., Tommiska, J., Vaaralahti, K., Dwyer, A., Gothilf, Y., Merlo, G. R., Santoni, F., Niederländer, N. J., … Pitteloud, N. (2020). Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism. American Journal of Human Genetics, 106(1), 58–70. https://doi.org/10.1016/j.ajhg.2019.12.003
Millar, A. C., Faghfoury, H., & Bieniek, J. M. (2021). Genetics of hypogonadotropic hypogonadism. Translational Andrology and Urology, 10(3), 1401–1409. https://doi.org/10.21037/tau.2020.03.33
Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., Raivio, T., Crowley, W. F., Seminara, S. B., Quinton, R., Hughes, V. A., Kumanov, P., Young, J., … Pitteloud, N. (2013). Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. American Journal of Human Genetics, 92(5), 725–743. https://doi.org/10.1016/j.ajhg.2013.04.008
Moalla, M., Hadj Kacem, F., Al-Mutery, A. F., Mahfood, M., Mejdoub-Rekik, N., Abid, M., Mnif-Feki, M., & Hadj Kacem, H. (2019). Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism. Journal of Assisted Reproduction and Genetics, 36(6), 1273–1280. https://doi.org/10.1007/s10815-019-01468-z
Naushad, A., & Kalra, P. (2022). Abstract 119: Neuron derived neurotropic factor- A novel gene implicated in congenital hypogonadotropic hypogonadism. Indian Journal of Endocrinology and Metabolism, 26(8), 51. https://doi.org/10.4103/2230-8210.363623
Neocleous, V., Fanis, P., Toumba, M., Tanteles, G. A., Schiza, M., Cinarli, F., Nicolaides, N. C., Oulas, A., Spyrou, G. M., Mantzoros, C. S., Vlachakis, D., Skordis, N., & Phylactou, L. A. (2020). GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature. Frontiers in Endocrinology, 11(August). https://doi.org/10.3389/fendo.2020.00626
Oleari, R., Massa, V., Cariboni, A., & Lettieri, A. (2021). The differential roles for neurodevelopmental and neuroendocrine genes in shaping GnRH neuron physiology and deficiency. International Journal of Molecular Sciences, 22(17), 9425.
Ortiz-Cabrera, N. V., Gavela-Pérez, T., Mejorado-Molano, F. J., Santillán-Coello, J. M., Villacampa-Aubá, J. M., Trujillo-Tiebas, M. J., & Soriano-Guillén, L. (2022). Diagnostic yield of clinical exome sequencing in congenital hypogonadotropic hypogonadism considering the degree of olfactory impairment. Anales de Pediatría (English Edition), 97(4), 247–254. https://doi.org/10.1016/j.anpede.2021.06.003
Pitteloud N, et al. Congenital hypogonadotropic hypogonadism:insight into the idiopathic form .Nat Rev Endocrine. 2019;15(10):610-628
Swee, D. S., & Quinton, R. (2019). Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males. Therapeutic advances in endocrinology and metabolism, 10, 2042018819826889.
Saleem, M., Khan, S. A., Khan, M. M. M., Suchal, Z. A., & Ram, N. (2023). Clinical and Biochemical Characteristics of Male Idiopathic Hypogonadotropic Hypogonadism Patients: A Retrospective Cross Sectional Study. International Journal of Fertility and Sterility, 17(1), 57–60. https://doi.org/10.22074/IJFS.2022.540499.1201
Šmigoc Schweiger, D., Davidović Povše, M., Trebušak Podkrajšek, K., Battelino, T., & Avbelj Stefanija, M. (2022). GNRHR-related central hypogonadism with spontaneous recovery – case report. Italian Journal of Pediatrics, 48(1), 1–5. https://doi.org/10.1186/s13052-022-01377-5
Stuckey, B. G. A., Jones, T. W., Ward, B. K., & Wilson, S. G. (2023). Digenic Congenital Hypogonadotropic Hypogonadism Due to Heterozygous GNRH1 p.R31C and AMHR2 p.G445_L453del Variants. Genes, 14(6). https://doi.org/10.3390/genes14061204
Sugiarto, A. M., & Soelistijo, S. A. (2022). A female with isolated hypogonadotropic hypogonadism: A case report and review article. Annals of Medicine and Surgery, 74(6), 103289. https://doi.org/10.1016/j.amsu.2022.103289
Swee, D. S., & Quinton, R. (2022). Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism. Expert Review of Endocrinology and Metabolism, 17(1), 47–61. https://doi.org/10.1080/17446651.2022.2023008
Sharma, A., Minhas, S., Dhillo, W. S., & Jayasena, C. N. (2021). Male infertility due to testicular disorders. The Journal of Clinical Endocrinology & Metabolism, 106(2), e442-e459.
Takashima, A., Yagi, S., Yamaguchi, K., Kurahashi, K., Kojima, Y., Zheng, R., Ise, T., Kusunose, K., Yoshida, S., Yamada, H., Soeki, T., Wakatsuki, T., Aihara, K. I., Akaike, M., & Sata, M. (2021). Congenital hypogonadotropic hypogonadism with early-onset coronary artery disease. Journal of Medical Investigation, 68(1.2), 189–191. https://doi.org/10.2152/jmi.68.189
Tamaoka, S., Suzuki, E., Hattori, A., Ogata, T., Fukami, M., & Katoh-Fukui, Y. (2021). NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism. Human Genome Variation, 8(1), 4–6. https://doi.org/10.1038/s41439-021-00137-x
Tang, R., Liu, X., Peng, Y., Ju, W., Hao, W., Peng, X., & Chen, R. (2020). Nectin-like molecule 2, a necessary sexual maturation regulator, participates in congenital hypogonadotropic hypogonadism. Gene, 754(June), 144885. https://doi.org/10.1016/j.gene.2020.144885
Winters, S. J. (2022). Congenital Hypogonadotropic Hypogonadism. A Case-Based Guide to Clinical Endocrinology, Third Edition, 1, 275–287. https://doi.org/10.1007/978-3-030-84367-0_31
Xu, C., Cassatella, D., van der Sloot, A. M., Quinton, R., Hauschild, M., De Geyter, C., Flück, C., Feller, K., Bartholdi, D., Nemeth, A., Halperin, I., Pekic Djurdjevic, S., Maeder, P., Papadakis, G., Dwyer, A. A., Marino, L., Favre, L., Pignatelli, D., Niederländer, N. J., … Pitteloud, N. (2018). Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants. Genetics in Medicine, 20(8), 872–881. https://doi.org/10.1038/gim.2017.197
Xu, C., & Pitteloud, N. (2019). Congenital Hypogonadotropic Hypogonadism (Isolated GnRH Deficiency). Contemporary Endocrinology, 229–250. https://doi.org/10.1007/978-3-030-11339-1_12
Young, J., Xu, C., Papadakis, G. E., Acierno, J. S., Maione, L., Hietamäki, J., ... & Pitteloud, N. (2019). Clinical management of congenital hypogonadotropic hypogonadism. Endocrine reviews, 40(2), 669-710.
Yu, B., Chen, K., Mao, J., Hou, B., You, H., Wang, X., Nie, M., Huang, Q., Zhang, R., Zhu, Y., Sun, B., Feng, F., Zhou, W., & Wu, X. (2022). The diagnostic value of the olfactory evaluation for congenital hypogonadotropic hypogonadism. Frontiers in Endocrinology, 13(September), 1–10. https://doi.org/10.3389/fendo.2022.909623
Zhang, L., Gao, Y., Du, Q., Liu, L., Li, Y., Dey, S. K., & Liao, Z. (2021). Genetic profiles and three-year follow-up study of Chinese males with congenital hypogonadotropic hypogonadism. The journal of sexual medicine, 18(9), 1500-1510.