DOI: https://doi.org/10.18370/2309-4117.2020.53.87-93

Chromosomal causes of hypergonadotropic hypogonadism in women and men. Literature review

О. А. Бурка, Л. П. Кузьмук, Г.О. Ісламова, С. В. Овчаренко

Abstract


Despite the relatively small portion in the structure of the infertility causes, hypergonadotropic hypogonadism (HH) is one of the greatest challenges in reproductive medicine. Diagnosis of HH chromosomal causes often occurs with a significant delay. This is due to the widespread stereotype of the necessary presence of typical phenotypic characters (eunuchoid habitus, pterygoid folds on the neck). This review deals with clinical recommendations for diagnosis of the most common chromosomal causes of HH in women (Turner syndrome (TS)) and in men (Klinefelter syndrome (KS)).

TS is a chromosomal pathology associated with the complete or partial absence of one X chromosome accompanied by one or more specific phenotypic features and comorbidities. Persons with suspected TS need to have karyotyping of at least 20 cells (venous blood material). This allows determining the karyotype 45,X, structural anomalies of X chromosome and mosaicism if it is present in more than 10% of the cells. If the mosaic form of TS is suspected but not diagnosed with standard karyotyping, options for investigating more cells or fluorescence hybridization in situ (FISH) are possible. It is important to verify the mosaic forms, especially in cases of a clone with Y chromosome in TS, since such a karyotype carries an increased risk of gonadoblastoma. FISH increases the diagnostic rate of mosaic forms of aneuploidy. Primary hypogonadism in men is the insufficiency of testosterone synthesis and spermatogenesis failure due to the pathology of gonads. Chromosomal causes of primary hypogonadism and nonobstructive azoospermia account for about 15% and are included in the mandatory list of diagnostic examinations. The variants of karyotypes in KS and their clinical manifestations are considered. KS is much more often diagnosed with delay compared to TS. The main diagnostic method for KS is karyotyping and using FISH to detect mosaic forms.

Thus, cytogenetic testing (karyotyping) is the first line of examination for women and men with primary (non-iatrogenic) HH; the use of FISH increases the diagnostics efficiency of mosaic forms of sex chromosome aneuploidy.


Keywords


hypergonadotropic hypogonadism; premature ovarian failure; amenorrhea; infertility; azoospermia; karyotyping; mosaicism; fluorescence in situ hybridization; FISH

References


Rasouli, M., McDaniel, K., Awadalla, M., Chung, K. “Mosaic Turner Syndrome Presenting with a 46,XY Karyotype.” Case Rep Obstet Gynecol (2019) 2019.

Layman, L.C. “Disorders of the hypothalamic-pituitary-gonadal axis.” In: Handbook of Neuroendocrinology. Elsevier Inc. (2012): 659–83.

Bonomi, M., et al. “Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism.” Journal of Endocrinological Investigation 40.2 (2017): 123–34.

Tsiligiannis, S., Panay, N., Stevenson, J.C. “Premature Ovarian Insufficiency and Long-Term Health Consequences.” Curr Vasc Pharmacol 17.6 (2019): 604–9.

Toth, B., et al. “Diagnosis and Therapy before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019). Part 1, Basic Assessment of the Woman.” Geburtshilfe Frauenheilkd 79.12 (2019): 1278–92.

Coccia, M.E., Rizzello, F., Orlandi, G. Assisted Reproductive Technologies. Springer. Cham (2020): 1–22.

Singh, N., Modi, D. “The Molecular Genetics of Testis Determination.” In: Genetics of Male Infertility. Springer International Publishing (2020): 3–17.

Adam, M.P., Manning, M.A. “The Genetics of Turner Syndrome.“ In: Turner Syndrome. Springer, Cham (2020): 13–31.

Webber, L., et al. “ESHRE Guideline: management of women with premature ovarian insufficiency.” Hum Reprod 31.5 (2016): 926–37.

Vujovic, S. “Premature ovarian insufficiency: an endocrine perspective.” Endocr Abstr (2018).

Nielsen, J., Wohlert, M. “Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus, Denmark.” Hum Genet 87.1 (1991): 81–3.

Iyer, N.P., Tucker, D.F., Roberts, S.H., et al. “Outcome of fetuses with Turner syndrome: A 10-year congenital anomaly register based study.” Journal of Maternal-Fetal and Neonatal Medicine 25.1 (2012): 68–73.

Zelinska, N., Shevchenko, I., Globa, E. “Nationwide study of turner syndrome in Ukrainian children: Prevalence, genetic variants and phenotypic features.” JCRPE J Clin Res Pediatr Endocrinol 10.3 (2018): 256–63.

Martin, R.H., Ko, E., Rademaker, A. “Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes.” Am J Med Genet 39.3 (1991): 321–31.

Byrne, J., Warburton, D., Kline, J., et al. “Morphology of early fetal deaths and their chromosomal characteristics.” Teratology 32.2 (1985): 297–315.

Hook, E.B., Warburton, D. “Turner syndrome revisited: Review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss.” Human Genetics 133.4 (2014): 417–24.

Gravholt, C.H., et al. “Clinical practice guidelines for the care of girls and women with Turner syndrome: Proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.” Eur J Endocrinol 177.3 (2017): G1–G70.

Morales-Hernández, A., et al. “Turner’s syndrome by mosaicism 45, X/46, XX/47, XXX associate to the Klippel-Feil syndrome.” Available from: [https://www.medigraphic.com/pdfs/bmhim/hi-2009/hii095h.pdf], last accessed Jun 12 2020.

Brambila-Tapia, A.J.L., Rivera, H., García-Castillo, H., et al. “47,XXX/45,X/46,XX mosaicism in a patient with Turner phenotype and spontaneous puberal development.” Fertil Steril 92.5 (2009): 1747.e5–1747.e7.

Schoemaker, M.J., Swerdlow, A.J., Higgins, C.D., et al. “Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study.” Lancet Oncol 9.3 (2008): 239–46.

Landin-Wilhelmsen, K., Bryman, I., Hanson, C., Hanson, L. “Short communication: Spontaneous pregnancies in a turner syndrome woman with Y-chromosome mosaicism.” J Assist Reprod Genet 21.6 (2004): 229–30.

Rogol, A.D. “Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis.” Am J Med Genet. Part C Semin Med Genet (2020): 31782.

Spatz, A., Borg, C., Feunteun, J. “X-chromosome genetics and human cancer.” Nature Reviews Cancer 4.8 (2004): 617–29.

Hildt, E., Graumann, S., eds. Genetics in Human Reproduction. Routledge (2018): 320 p.

Galupa, R., Heard, E. “X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation.” Annu Rev Genet 52.1 (2018): 535–66.

Noordman, I.D., et al. “Karyotype - Phenotype Associations in Patients with Turner Syndrome.” Pediatr Endocrinol Rev 16.4 (2019): 431–40.

Oktay, K., et al. “Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines.” Journal of Pediatric and Adolescent Gynecology 29.5 (2016): 409–16.

Pasquino, A.M., Passeri, F., Pucarelli, I., et al. “Spontaneous Pubertal Development in Turner’s Syndrome 1.” J Clin Endocrinol Metab 82.6 (1997): 1810–13.

Elsheikh, M., Dunger, D.B., Conway, G.S., Wass, J.A.H. “Turner’s Syndrome in Adulthood.” Endocr Rev 23.1 (2002): 120–40.

Dabrowski, E., Jensen, R., Johnson, E.K., et al. “Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype.” Horm Res Paediatr 92.3 (2019): 143–9.

Venn, A., Watson, L.F., Hemminki, E., et al. “Mortality in a cohort of IVF patients.” Hum Reprod 16.12 (2001): 782–8.

Finlayson, C., Bernardi, L., Habiby, R. “Fertility Preservation for Turner Syndrome.” In: Turner Syndrome. Springer International Publishing (2020): 79–91.

Calanchini, M., Bradley-Watson, J., Orchard, E., Turner, H.E. “Maternal cardiovascular risk and pregnancy outcomes in turner syndrome - new evidence supports current guidance,” Endocr. Abstr., Nov. 2019.

Wolff, D.J., Van Dyke, D.L., Powell, C.M. “Laboratory guideline for Turner syndrome.” Genetics in Medicine 12.1 (2010): 52–5.

Wiktor A.E., Van Dyke, D.L. “Detection of low level sex chromosome mosaicism in Ullrich-Turner syndrome patients.” Am J Med Genet. Part A 138A.3 (2005): 259–61.

European Association of Urology. EAU Guidelines: Male Hypogonadism. Available from: [https://uroweb.org/guideline/male-hypogonadism], last accessed Jun 12 2020.

European Association of Urology. EAU Guidelines: Male Infertility. Available from: [https://uroweb.org/guideline/male-infertility], last accessed Jun 08 2020.

Fakhro, K.A., Robay, A., Rodriguez-Flores, J.L., Crystal, R.G. “Genetic Evaluation of Male Infertility.” In: Genetics of Male Infertility. Springer International Publishing (2020): 95–118.

Martinez, M.P., Elbardisi, H., Majzoub, A., Arafa, M. “Klinefelter Syndrome.” In: Genetics of Male Infertility. Cham. Springer International Publishing (2020): 189–205.

Morris, J.K., Alberman, E., Scott, C., Jacobs, P. “Is the prevalence of Klinefelter syndrome increasing?” Eur J Hum Genet 16.2 (2008): 163–170.

Bojesen, A., Juul, S., Gravholt, C.H. “Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study.” J Clin Endocrinol Metab 88.2 (2003): 622–6.

Urhoj, S.K., Raaschou-Nielsen, O., Hansen, A.V., et al. “Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study.” Int J Cancer 140.11 (2017): 2461–72.

Bojesen, A., et al. “The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism.” Diabetes Care 29.7 (2006): 1591–8.

Lanfranco, F., Kamischke, A., Zitzmann, M., Nieschlag, P.E. “Klinefelter’s syndrome.” Lancet 364.9430 (2004): 273–83.

Bojesen, A., Groth, K., Høst, C., Skakkeb’k, A. “The role of hypogonadism in Klinefelter Syndrome.” Asian J Androl 16.2 (2014): 185.

Bojesen, A., Høst, C., Gravholt, C.H. “Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition.” Molecular Human Reproduction 16.6 (2010): 396–401. DOI: 10.1093/molehr/gaq016

Bojesen, A., Juul, S., Birkebæk, N.H., Gravholt, C.H. “Morbidity in Klinefelter Syndrome: A Danish Register Study Based on Hospital Discharge Diagnoses.” J Clin Endocrinol Metab 91.4 (2006): 1254–60.

Lee, H.S., Park, C.W., Lee, J.S., Seo, J.T. “Hypogonadism makes dyslipidemia in Klinefelter’s syndrome.” J Korean Med Sci 32.11 (2017): 1848–51.

Fricke, G.R., Mattern, H.J., Schweikert, H.U., Schwanitz, G. “Klinefelter’s syndrome and mitral valve prolapse. An echocardiographic study in twenty-two patients.” Biomed Pharmacother 38.2 (1984): 88–97.

Swerdlow, A., et al. “Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study.” JNCI: Journal of the National Cancer Institute 97.16 (2005): 1204–10. DOI: 10.1093/jnci/dji240

Fainberg, J., Hayden, R.P., Schlegel, P.N. “Fertility management of Klinefelter syndrome.” Expert Review of Endocrinology and Metabolism 14.6 (2019): 369–80.

Regadera, J., Codesal, J., Paniagua, R., et al. “Immunohistochemical and quantitative study of interstitial and intratubular leydig cells in normal men, cryptorchidism, and Klinefelter’s syndrome.” J Pathol 164.4 (1991): 299–306.

Wikström, A.M., Dunkel, L. “Testicular Function in Klinefelter Syndrome.” Horm Res Paediatr 69.6 (2008): 317–26.

Plotton, I., et al. “Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with nonmosaic 47,XXY Klinefelter syndrome.” J Clin Endocrinol Metab 100.3 (2015): 961–7.

Masterson, T.A., Nassau, D.E., Ramasamy, R. “A clinical algorithm for management of fertility in adolescents with the Klinefelter syndrome.” Curr Opin Urol 30.3 (2020): 324–7.

Tanos, V., Gajek, A., Elsemary, M.Y., et al. “Klinefelter Syndrome: Review of the Literature Comparing TESE and mTESE, Sperm Retrieval and Pregnancy Rate.” Int J Reprod Med Gynecol 4.1 (2018): 012–16.


GOST Style Citations


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2.            Layman, L.C. “Disorders of the hypothalamic-pituitary-gonadal axis.” In: Handbook of Neuroendocrinology. Elsevier Inc. (2012): 659–83.

3.            Bonomi, M., et al. “Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism.” Journal of Endocrinological Investigation 40.2 (2017): 123–34.

4.            Tsiligiannis, S., Panay, N., Stevenson, J.C. “Premature Ovarian Insufficiency and Long-Term Health Consequences.” Curr Vasc Pharmacol 17.6 (2019): 604–9.

5.            Toth, B., et al. “Diagnosis and Therapy before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019). Part 1, Basic Assessment of the Woman.” Geburtshilfe Frauenheilkd 79.12 (2019): 1278–92.

6.            Coccia, M.E., Rizzello, F., Orlandi, G. Assisted Reproductive Technologies. Springer. Cham (2020): 1–22.

7.            Singh, N., Modi, D. “The Molecular Genetics of Testis Determination.” In: Genetics of Male Infertility. Springer International Publishing (2020): 3–17.

8.            Adam, M.P., Manning, M.A.  “The Genetics of Turner Syndrome.“ In: Turner Syndrome. Springer, Cham (2020): 13–31.

9.            Webber, L., et al. “ESHRE Guideline: management of women with premature ovarian insufficiency.” Hum Reprod 31.5 (2016): 926–37.

10.          Vujovic, S. “Premature ovarian insufficiency: an endocrine perspective.” Endocr Abstr (2018).

11.          Nielsen, J., Wohlert, M. “Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus, Denmark.” Hum Genet 87.1 (1991): 81–3.

12.          Iyer, N.P., Tucker, D.F., Roberts, S.H., et al. “Outcome of fetuses with Turner syndrome: A 10-year congenital anomaly register based study.” Journal of Maternal-Fetal and Neonatal Medicine 25.1 (2012): 68–73.

13.          Zelinska, N., Shevchenko, I., Globa, E. “Nationwide study of turner syndrome in Ukrainian children: Prevalence, genetic variants and phenotypic features.” JCRPE J Clin Res Pediatr Endocrinol 10.3 (2018): 256–63.

14.          Martin, R.H., Ko, E., Rademaker, A. “Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes.” Am J Med Genet 39.3 (1991): 321–31.

15.          Byrne, J., Warburton, D., Kline, J., et al. “Morphology of early fetal deaths and their chromosomal characteristics.” Teratology 32.2 (1985): 297–315.

16.          Hook, E.B., Warburton, D. “Turner syndrome revisited: Review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss.” Human Genetics 133.4 (2014): 417–24.

17.          Gravholt, C.H., et al. “Clinical practice guidelines for the care of girls and women with Turner syndrome: Proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.” Eur J Endocrinol 177.3 (2017): G1–G70.

18.          Morales-Hernández, A., et al. “Turner’s syndrome by mosaicism 45, X/46, XX/47, XXX associate to the Klippel-Feil syndrome.” Available from: [https://www.medigraphic.com/pdfs/bmhim/hi-2009/hii095h.pdf], last accessed Jun 12 2020.

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20.          Schoemaker, M.J., Swerdlow, A.J., Higgins, C.D., et al. “Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study.” Lancet Oncol 9.3 (2008): 239–46.

21.          Landin-Wilhelmsen, K., Bryman, I., Hanson, C., Hanson, L. “Short communication: Spontaneous pregnancies in a turner syndrome woman with Y-chromosome mosaicism.” J Assist Reprod Genet 21.6 (2004): 229–30.

22.          Rogol, A.D. “Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis.” Am J Med Genet. Part C Semin Med Genet (2020): 31782.

23.          Spatz, A., Borg, C., Feunteun, J. “X-chromosome genetics and human cancer.” Nature Reviews Cancer 4.8 (2004): 617–29.

24.          Hildt, E., Graumann, S., eds. Genetics in Human Reproduction. Routledge (2018): 320 p.

25.          Galupa, R., Heard, E. “X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation.” Annu Rev Genet 52.1 (2018): 535–66.

26.          Noordman, I.D., et al. “Karyotype - Phenotype Associations in Patients with Turner Syndrome.” Pediatr Endocrinol Rev 16.4 (2019): 431–40.

27.          Oktay, K., et al. “Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines.” Journal of Pediatric and Adolescent Gynecology 29.5 (2016): 409–16.

28.          Pasquino, A.M., Passeri, F., Pucarelli, I., et al. “Spontaneous Pubertal Development in Turner’s Syndrome 1.” J Clin Endocrinol Metab 82.6 (1997): 1810–13.

29.          Elsheikh, M., Dunger, D.B., Conway, G.S., Wass, J.A.H. “Turner’s Syndrome in Adulthood.” Endocr Rev 23.1 (2002): 120–40.

30.          Dabrowski, E., Jensen, R., Johnson, E.K., et al. “Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype.” Horm Res Paediatr 92.3 (2019): 143–9.

31.          Venn, A., Watson, L.F., Hemminki, E., et al. “Mortality in a cohort of IVF patients.” Hum Reprod 16.12 (2001): 782–8.

32.          Finlayson, C., Bernardi, L., Habiby, R. “Fertility Preservation for Turner Syndrome.” In: Turner Syndrome. Springer International Publishing (2020): 79–91.

33.          Calanchini, M., Bradley-Watson, J., Orchard, E., Turner, H.E. “Maternal cardiovascular risk and pregnancy outcomes in turner syndrome - new evidence supports current guidance,” Endocr. Abstr., Nov. 2019.

34.          Wolff, D.J., Van Dyke, D.L., Powell, C.M. “Laboratory guideline for Turner syndrome.” Genetics in Medicine 12.1 (2010): 52–5.

35.          Wiktor A.E., Van Dyke, D.L. “Detection of low level sex chromosome mosaicism in Ullrich-Turner syndrome patients.” Am J Med Genet. Part A 138A.3 (2005): 259–61.

36.          European Association of Urology. EAU Guidelines: Male Hypogonadism. Available from: [https://uroweb.org/guideline/male-hypogonadism], last accessed Jun 12 2020.

37.          European Association of Urology. EAU Guidelines: Male Infertility. Available from: [https://uroweb.org/guideline/male-infertility], last accessed Jun 08 2020.

38.          Fakhro, K.A., Robay, A., Rodriguez-Flores, J.L., Crystal, R.G. “Genetic Evaluation of Male Infertility.” In: Genetics of Male Infertility. Springer International Publishing (2020): 95–118.

39.          Martinez, M.P., Elbardisi, H., Majzoub, A., Arafa, M. “Klinefelter Syndrome.” In: Genetics of Male Infertility. Cham. Springer International Publishing (2020): 189–205.

40.          Morris, J.K., Alberman, E., Scott, C., Jacobs, P. “Is the prevalence of Klinefelter syndrome increasing?” Eur J Hum Genet 16.2 (2008): 163–170.

41.          Bojesen, A., Juul, S., Gravholt, C.H. “Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study.” J Clin Endocrinol Metab 88.2 (2003): 622–6.

42.          Urhoj, S.K., Raaschou-Nielsen, O., Hansen, A.V., et al. “Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study.” Int J Cancer 140.11 (2017): 2461–72.

43.          Bojesen, A., et al. “The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism.” Diabetes Care 29.7 (2006): 1591–8.

44.          Lanfranco, F., Kamischke, A., Zitzmann, M., Nieschlag, P.E. “Klinefelter’s syndrome.” Lancet 364.9430 (2004): 273–83.

45.          Bojesen, A., Groth, K., Høst, C., Skakkeb’k, A. “The role of hypogonadism in Klinefelter Syndrome.” Asian J Androl 16.2 (2014): 185.

46.          Bojesen, A., Høst, C., Gravholt, C.H. “Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition.” Molecular Human Reproduction 16.6 (2010): 396–401. DOI: 10.1093/molehr/gaq016

47.          Bojesen, A., Juul, S., Birkebæk, N.H., Gravholt, C.H. “Morbidity in Klinefelter Syndrome: A Danish Register Study Based on Hospital Discharge Diagnoses.” J Clin Endocrinol Metab 91.4 (2006): 1254–60.

48.          Lee, H.S., Park, C.W., Lee, J.S., Seo, J.T. “Hypogonadism makes dyslipidemia in Klinefelter’s syndrome.” J Korean Med Sci 32.11 (2017): 1848–51.

49.          Fricke, G.R., Mattern, H.J., Schweikert, H.U., Schwanitz, G. “Klinefelter’s syndrome and mitral valve prolapse. An echocardiographic study in twenty-two patients.” Biomed Pharmacother 38.2 (1984): 88–97.

50.          Swerdlow, A., et al. “Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study.” JNCI: Journal of the National Cancer Institute 97.16 (2005): 1204–10. DOI: 10.1093/jnci/dji240

51.          Fainberg, J., Hayden, R.P., Schlegel, P.N. “Fertility management of Klinefelter syndrome.” Expert Review of Endocrinology and Metabolism 14.6 (2019): 369–80.

52.          Regadera, J., Codesal, J., Paniagua, R., et al. “Immunohistochemical and quantitative study of interstitial and intratubular leydig cells in normal men, cryptorchidism, and Klinefelter’s syndrome.” J Pathol 164.4 (1991): 299–306.

53.          Wikström, A.M., Dunkel, L. “Testicular Function in Klinefelter Syndrome.” Horm Res Paediatr 69.6 (2008): 317–26.

54.          Plotton, I., et al. “Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with nonmosaic 47,XXY Klinefelter syndrome.” J Clin Endocrinol Metab 100.3 (2015): 961–7.

55.          Masterson, T.A., Nassau, D.E., Ramasamy, R. “A clinical algorithm for management of fertility in adolescents with the Klinefelter syndrome.” Curr Opin Urol 30.3 (2020): 324–7.

56.          Tanos, V., Gajek, A., Elsemary, M.Y., et al. “Klinefelter Syndrome: Review of the Literature Comparing TESE and mTESE, Sperm Retrieval and Pregnancy Rate.” Int J Reprod Med Gynecol 4.1 (2018): 012–16.





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