E.M. ORESHKINA, N.YU. RAYGORODSKAYA, N.V. BOLOTOVA, N.Y. FILINA

 Saratov State Medical University named after V.I. Rasumovskiy, Saratov

 Contact details:

Oreshkina E.M. — post-graduate student of the Department of Propedeutics of Children’s Diseases, Pediatric Endocrinology and Diabetology

Address: 112 Bolshaya Kazachya St., Saratov, Russian Federation, 410012, tel.: +7-986-992-53-57, e-mail: elen.oreshkina@mail.ru

Bilateral cryptorchidism is a common symptom of congenital gonadotropin deficiency. Detection of congenital hypogonadotropic hypogonadism (CHH) at an early age is important for preventing the long delayed puberty and timely initiation of therapy.

The purpose — to identify СHH in boys with bilateral cryptorchidism based on hormonal examinations during mini-puberty.

Material and methods. We present five clinical cases of patients with bilateral cryptorchidism, with CHH diagnosed in mini-puberty. The examination of 1–6 months old boys included tests of serum LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B. To assess the pituitary gonadotropic function, a test with a Gn-RH analogue was performed. Patients with established CHH underwent molecular genetic testing.

Results. The basis for СHH identification were the low serum concentrations of gonadotropins, AMH, testosterone, and inhibin B in boys with bilateral cryptorchidism during mini-puberty. Mutations in the FGF8 and SPRY4 genes associated with CHH were detected in 2 patients. CHH as part of hypopituitarism was revealed in 2 boys.

Conclusions. Hormonal examination of boys with bilateral cryptorchidism during mini-puberty allows establishing gonadotropin deficiency at an early age, to carry out a long-term control for patients, and to begin treatment timely.

Hormonal examination during mini-puberty can be the basis for diagnosing both isolated CHH and congenital hypopituitarism.

Key words: bilateral cryptorchidism, congenital hypogonadotropic hypogonadism, mini-puberty.

 (For citation: Oreshkina E.M., Raygorodskaya N.Yu., Bolotova N.V., Filina N.Y. Bilateral cryptorchidism as a clinical marker for early diagnostics of congenital gonadotropin deficiency: clinical cases. Practical medicine. 2023. Vol. , № , P.)

 REFERENCES

1.           Elamo H.P., Virtanen H.E., Toppari J. Genetics of cryptorchidism and testicular regression. Best Practice and Research: Clinical Endocrinology and Metabolism, 2022, vol. 36 (1), p. 101619. DOI: 10.1016/j.beem.2022.101619

2.           Rodprasert W., Virtanen H.E., Mäkelä J.A., Toppari J. Hypogonadism and Cryptorchidism. Front Endocrinol (Lausanne), 2019, vol. 10, p. 906. DOI: 10.3389/fendo.2019.00906

3.           Grumbach M.M. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab, 2005, vol. 90 (5), pp. 3122–3127. DOI: 10.1210/jc.2004-2465

4.           Hietamaki J., Karkinen J., Iivonen A.P. et al. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years. eClinical Medicine, 2022, vol. 51, p. 101556. DOI: 10.1016/j.eclinm.2022.101556

5.           Grinspon R.P., Castro S., Brunello F.G. et al. Diagnosis of Male Central Hypogonadism During Childhood. J Endocr Soc, 2021, vol. 5 (11), pp. 1–8. DOI: 10.1210/jendso/bvab145

6.           Varimo T., Hero M., Laitinen E.M. et al. Health-related quality of life in male patients with congenital hypogonadotropic hypogonadism. Clin Endocrinol (Oxf), 2015, vol. 83 (1), pp. 141–143.

7.           Renault C.H., Aksglaede L., Wojdemann D. et al. Minipuberty of human infancy — A window of opportunity to evaluate hypogonadism and differences of sex development? Ann Pediatr Endocrinol Metab, 2020, vol. 25, pp. 84–91. DOI: 10.6065/apem.2040094.047

8.           Lucaccioni L., Trevisani V., Boncompagni A. et al. Minipuberty: Looking Back to Understand Moving Forward. Front. Pediatr, 2021, vol. 8, pp. 1–11. DOI: 10.3389/fped.2020.612235

9.           Grinspon R.P., Ropelato M.G., Gottlieb S. et al. Basal follicle-stimulating hormone and peak gonadotropin levels after gonadotropin-releasing hormone infusion show high diagnostic accuracy in boys with suspicion of hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology and Metabolism, 2010, vol. 6 (95), pp. 2811–2818.

10.         Harrington J., Palmert M.R. Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. The Journal of Clinical Endocrinology and Metabolism, 2012, vol. 9 (97), pp. 3056–3067.

11.         Swee D.S., Quinton R. Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males. Ther Adv Endocrinol Metab, 2019, vol. 10, pp. 1–15. DOI: 10.1177/204201881982688

12.         Trabado S., Maione L., Bry-Gauillard H. et al. Insulin-like Peptide 3 (INSL3) in Men With Congenital Hypogonadotropic Hypogonadism / Kallmann Syndrome and Effects of Different Modalities of Hormonal Treatment: A Single-Center Study of 281 Patients. J Clin Endocrinol Metab, 2014, vol. 99 (2), pp. 268–275.

13.         Vizeneux A., Hilfiger A., Bouligand J. et al. Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys. PLoS ONE, 2013, vol. 8 (10), p. e77827. DOI: 10.1371/journal.pone.0077827

14.         Montenegro L.R., Silveira L.F.G., Tusset C. et al. Combined use of multiplex ligation-dependent probe amplification and automatic sequencing for identification of KAL1 defects in patients with Kallmann syndrome. Reproductive Endocrinology, 2013, vol. 100, pp. 854–859. DOI: 10.1016/j.fertnstert.2013.04.045

15.         Main K.M., Schmidt I.M., Skakkebæk N.E. A Possible Role for Reproductive Hormones in Newborn Boys: Progressive Hypogonadism without the Postnatal Testosterone Peak. The Journal of Clinical Endocrinology & Metabolism, 2000, vol. 12 (1), pp. 4905–4907.

16.         Boukari K., Meduri G., Brailly-Tabard S. et al. Lack of androgen receptor expression in Sertoli cells accounts for the absence of anti-Mullerian hormone repression during early human testis development. Clin Endocrinol Metab, 2009, vol. 94 (5), pp. 1818–1825. DOI: 10.1210/jc.2008-1909

17.         Grinspon R.P., Rey R.A. Anti-Müllerian Hormone and Sertoli Cell Function in Paediatric Male Hypogonadism. Horm Res Paediatr, 2010, vol. 73, pp. 81–92. DOI: 10.1159/000277140

18.         Pitteloud N., Hayes F.J., Boepple P.A. et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab, 2002, vol. 87 (1), pp. 152–160.

19.         Young J., Xu C., Papadakis G.E. et al. Clinical Management of Congenital Hypogonadotropic Hypogonadism. Endocr Rev, 2019, vol. 40 (2), pp. 669–710. DOI: 10.1210/er.2018-00116

20.         Trarbach E.B., Abreu A.P., Silveira L.F. et al. Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. J Clin Endocrinol Metab, 2010, vol. 95 (7), pp. 3491–3496. DOI: 10.1210/jc.2010-0176

21.         Falardeau J., Chung W.C., Beenken A. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest, 2008, vol. 118 (8), pp. 2822-2831. DOI: 10.1172/JCI34538

22.         Riley B.M., Mansilla M.A., Ma J. et al. Impaired FGF signaling contributes to cleft lip and palate. Proc. Natl. Acad. Sci. USA, 2007, vol. 104, pp. 4512–4517. DOI: 10.1073/pnas.0607956104

23.         Perantoni A.O., Timofeeva O., Naillat F. et al. Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development, 2005, vol. 132 (17), pp. 3859–3871. DOI: 10.1242/dev.01945

24.         Nerli R.B. Penile growth in response to hormone treatment in children with micropenis. Indian journal of urology. Journal of the Urological Society of India, 2013, vol. 4 (29), pp. 288–291.

25.         Papadimitriou D.T., Chrysis D., Nyktari G. et al. Replacement of male mini-puberty. J Endocr Soc, 2019, vol. 3 (7), pp. 1275–1282. DOI: 10.1210/js.2019-00083

26.         Indirli R., Cangiano B., Profka E. et al. A Rare SPRY4 Gene Mutation Is Associated With Anosmia and Adult-Onset Isolated Hypogonadotropic Hypogonadism. Front Endocrinol (Lausanne), 2019, vol. 10, p. 781. DOI: 10.3389/fendo.2019.00781

27.         Taniguchi K., Ayada T., Ichiyama K. et al. Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling.  Biochem. Biophys. Res. Commun, 2007, vol. 352, pp. 896–902.

28.         Braslavsky D., Grinspon R.P., Ballerini M.G. et al. Hypogonadotropic Hypogonadism in Infants with Congenital Hypopituitarism: A Challenge to Diagnose at an Early Stage. Horm Res Paediatr, 2015, vol. 84, pp. 289–297. DOI: 10.1159/000439051